SK80397A3 - Substituted azetidin-2-ones, preparation method thereof, farmaceutical compositions and their use - Google Patents

Abstract

Compounds of formula (I) in which R<1> and R<2>, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl; R<3> is aryl or arylC(1-4)alkyl which may be optionally substituted; X is a linker group; Y is an optionally substituted aryl group; and n is 0, 1 or 2; are inhibitors of the enzyme Lp-PLA2 and thereof of use in treating atherosclerosis.

Description

Technical field

The invention relates to certain novel monocyclic β-lactam compounds, processes for their preparation, suitable intermediates in their preparation, pharmaceutical compositions containing said compounds and their use in therapy, particularly for the treatment of atherosclerosis.

BACKGROUND OF THE INVENTION

Lipoprotein associated phospholipase A2 (Lp-PLA2). The sequence of said enzyme, its isolation and purification, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding said enzyme are described in patent application WO 95/00649 (SmithKline Beecham plc). Intended therapeutic uses of inhibitors of said enzyme include atherosclerosis, diabetes, rheumatoid arthritis, defeat, myocardial infarction, reperfusion cases, acute and chronic inflammations. A later patent application (WO 95/09921, Icos Corporation) and a similar publication in Nature (Tjoelker et al., 374,549 (1995)) describe the same enzyme, although they call it platelet acetyl hydrolase (PAF acetyl hydrolase) activation factor and suggest, It may be an effective protein for the control of pathological inflammatory events.

is an important lysophosphatidylcholine, in the conversion of phosphatidylcholine to the conversion of low density lipoprotein (LDL) to its oxidized form. This enzyme is known to hydrolyze a sn-2 ester of oxidized phosphatidyl choline to form lysophosphatidylcholine and an oxidatively modified fatty acid. Both Lp-PLA _{2 products} are biologically active and lysophosphatidylcholine, which is a component of oxidized LDL, is known as a potential chemoatrac- 2.

tant in circulating monocytes. As such, lysophosphatidylcholine is believed to play an important role in atherosclerosis by being responsible for the accumulation of cholesterol ester loaded cells in the arteries. Thus, Q inhibition of Lp-PLA ₂ could be expected to stop the formation of these macrophage-enriched lesions, inhibiting the formation of lysophosphatidylcholine and oxidized free fatty acids, and thus be useful in the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidatively modified LDL is also believed to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Lp-PLA ₂ inhibitors may therefore prove effective in the treatment of these diseases. The Lp-PLA ₂ inhibitor can also be used in other disease states characterized by endothelial dysfunction including diabetes, hypertension, angina and after ischemia and reperfusion.

Lp-PLA ₂ inhibitors may also be of general use in any disease characterized by activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA _2. Examples of such diseases include psoriasis.

Lp-PLA ₂ inhibitors may also be of general use in any disease involving lipid peroxidation in conjunction with the effect of Lp-PLA ₂ to produce two harmful products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions of atherosclerosis, diabetes, rheumatoid arthritis, defeat, brain inflammatory conditions such as Alzheimer's disease, myocardial infarction, reperfusion cases, sepsis, acute and chronic inflammatory diseases. Further, such conditions include various neuropsychiatric disorders, such as schizophrenia (see Psychopharmocology Bulletin 31, 159-165 (1995)).

SUMMARY OF THE INVENTION

A number of compounds have been identified as acting as inhibitors of Lp-PLA2 at present.

The present invention provides a compound having the formula (I):

S (O) n R ^{3 N} \ o ^X

CH ₂ —XY

in which:

r! a, which may be the same or different, is each selected from the group consisting of hydrogen, halogen or optionally substituted C 1-6 alkyl;

R 1 is aryl or aryl C 1-4 alkyl which may be optionally substituted;

X is a linking group;

Y is an optionally substituted aryl group; and n is 0, 1 or 2.

The compounds of formula (I) are inhibitors of Lp-PLA ₂ and are expected to be useful in the treatment of atherosclerosis and other diseases mentioned above.

Typical examples of R and R include hydrogen, methyl and ethyl, optionally substituted with hydroxyl. R and R each are suitably 19 H 19, or one of ^Rx and Ry is hydrogen and the other of R ^X and R is methyl (to give a trans-methyl). It is preferred that R ³ and R 3 are each hydrogen.

ABOUT

Typical examples of the aryl group for R include phenyl and naphthyl groups. A suitable aryl group is R ^ _ ^ ₃ alkyl. Suitable examples of the group include phenyl, benzyl, 2-phenylethyl and 3-phenylpropyl, and in each of them, the phenyl ring may be optionally substituted with up to three substituents. It will be appreciated that the optional substituent may be in position on the aryl moiety and / or on the alkyl moiety (if any and this is present). Preferred is optionally substituted benzyl, preferably substituted in the 4-position. Suitable substituents

About the phenyl or naphthyl ring of R include halogen, hydroxy, C ^ ₁ _g alkyl, C (- £ _6) alkoxy,

Even more preferably, 4-carboxybenzyl or its corresponding

n is preferably 1 or 2, more preferably 1.

S (O) _n R 6 is preferably optionally substituted benzylsulfinyl, more preferably 4-carboxybenzylsulfinyl or a corresponding

Suitable X is a direct bond; a group X '(CH ₂ ) _m wherein X' is CO, CONR ⁵ , COO, CONR ⁵ CO, or CONHO, wherein R ⁵ is hydrogen or C 1-6 alkyl and m is 0 or an integer from 1 to 12; or C ^ _ ₁₂₎ alkylene chain optionally interupted by X '. Typical examples of X include CO (CH ₂ ) _m , CONH (CH ₂ ) _m , COO (CH ₂ ) _m , CONHCO (CH ₂ ) _m , CONHO (CH ₂ ) _m, and C 1-4 alkylene. X 'is preferably CO or CONR $, more preferably CONH. m is preferably 1, 2, 5, 6, 7 or 9, preferably 6. Preferably X is CONH (CH ₂ ) g.

Y is preferably a benzene ring, optionally substituted with up to three substituents. Suitable substituents include halogen, hydroxy, C 1-6 alkyl and C 1-6 alkoxy. Suitable Y is optionally substituted with halogen, more preferably 4-chloro or 4-fluorophenyl, most preferably 4-fluorophenyl.

It will be readily understood by those skilled in the art that the C-4 β-lactam ring forms a chiral center that gives rise to the formation of stereoisomers. The present invention includes all such stereoisomers.

It will further be appreciated by those skilled in the art that in the compounds of formula (I) in which n is 1 and which are sulphoxide compounds, the presence of the SO moiety forms an additional chiral center of the molecule and therefore affords the possibility of further stereoisomers. The present invention includes all said stereoisomers.

In the compounds of formula (I), the mutual configuration on the C-4 and SO moieties of R, S and S, R is preferred, and in the most preferred compounds the absolute configuration on the C-4 and SO moieties of R or S is preferred.

As used herein, the term alkyl and similar terms to alkoxy include all isomers

branched or unbranched chain. Typical examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

Suitable substituents for alkyl include for example halogen, cyano, azido, nitro, carboxy, (C _g _L) alkoxycarbonyl, carbamoyl, mono- or di- (C ^ _g) alkylcarbamoyl, carbamoyl, sulfo, sulfamoyl, mono- or di- ( C 1-6 alkylsulfamoyl, amino, mono- or di- (C 1-6) alkylamino, acylamino, ureido, (C 1-6) alkylcarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C 1-6) ₍ 1g) alkoxy, acyloxy, acyl, 2-thienoyl, (C 1-6 alkylthio, (C 1-6) alkylsulfinyl, (C 1-6) alkylsulfonyl, hydroxyimino, (C 1-6) alkoxyimino, hydrazino, hydrazono , benzhydroxymoyl, guanidino, amidino and iminoalkylamino.

As used herein, the term aryl includes, unless otherwise indicated, phenyl or naphthyl optionally substituted with up to five, preferably up to three, substituents.

Suitable aryl substituents include, for example, halogen, cyano, (C 1-6) alkyl, (C 1-6) cycloalkyl, (C 1-6) alkoxy, halogen (C 1-6) alkyl, hydroxy, amino, mono- di- (C 1-6) groups. ) alkylamino, acylamino, nitro, carboxy, (C £ _g) alkoxycarbonyl, (C2_g) alkenyloxycarbonyl, (C2_g) alkoxycarbonyl (C ₁ _g) alkyl, (C ₂ _g) alkenoxycarbonyl (C ^) alkyl, (C ₁ _g) alkylcarbonyloxy, carboxy (C ^ _) alkoxy, (C £ _ g) alkoxycarbonyl (Ci_g) alkoxy, (C2_g) alkenoxycarbonyl (C ^ _g) alkoxy, (C ^ _g) alkylcarbonyloxy, (C ₁ _g) alkylthio , (C ^ _g) alkylsulfinyl, (C _g _L) alkylsulfonyl, sulfamoyl, mono- and di (C ^ g) alkylsulfamoyl, carbamoyl, mono- and di- (C £ _g) alkylcarbamoyl, and heterocyclyl.

The term halogen as used herein includes fluorine, chlorine, bromine and iodine.

Preferred compounds of formula (I) include: (47 R, SS / 4 S, S 7 R) -N- (6-phenylhexyl) - (4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide;

(47 R, S 5/45, S 7 R) -N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide;

(4R, SS / 4S, SS) -N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide;

(4R, SS / 4S, SSR) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutylazetidin-2-one);

(4R, SS) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one;

(4R, SS / 4S, SSR) -4- (3,4-dimethoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one;

(4R, SS / 4S, SSR) -4- (3-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one;

(4R, SS / 4S, SS) -4- (4-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one;

(R, S / S, 7R) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methyl-phenyl) -sulfinyl-2-oxo-azetidin-1-yl-acetamide;

(R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl) 2-oxo-azetidin-1-yl-acetamide;

(+) - (1 R, 5 or S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl) -2-oxo-azetidin-1-yl-acetamide; (-) - (R, S or S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl) -2-oxo-azetidin-1-yl-acetamide;

(R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methoxy-phenylsulfinyl) -2-oxo-azetidin-1-yl-acetamide;

N- (6- (4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl) -2-oxo-azetidin-1-yl-acetamide (diastereoisomer 2);

N- (6- {4-fluorophenyl) hexyl) -4- (4-carboxybenzylsulphinyl) -2-oxo-azetidin-1-yl-acetamide (Diasteroisomer 2);

N- (6- {4-fluorophenyl) hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl) -2-oxo-azetidin-1-yl-acetamide (Diasteroisomer 2);

N- (6- {4-fluorophenyl) hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl) -2-oxo-azetidin-1-yl-acetamide (Diasteroisomer 2);

N- (6- {4-fluorophenyl) hexyl] - [4- (4-ethyloxycarbonylbenzylsulphinyl) -2-oxo-azetidin-1-yl-acetamide (Diasteroisomer 2);

N- (6- {4-fluoro-phenyl} hex-l-yl) -4- (4-carboxybenzylthio) -2-oxo-azetidin-l-yl-acetamide;

N- (6- {4-fluorophenyl) hexyl) - [4- (4-methyloxycarbonylbenzyl) sulfinyl-2-oxo-azetidin-1-yl] -acetamide (Diasteroisomer 2);

N- (6- {4-chlorophenyl) hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxo-azetidin-1-yl) -acetamide (Diasteroisomer 2);

N- (6- {4-chlorophenyl} hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxo-azetidin-1-yl) acetamide (Diasteroisomer 2);

N- (6- {4-chlorophenyl} hexyl) -4- (4-ethyloxycarbonylbenzylsulphinyl-2-oxo-azetidin-1-yl) -acetamide (diasteroisomer 2);

N- [6- (4-Fluorophenyl) hexyl] - [4- (4-allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxo-azetidin-1-yl] -acetamide (Diasteroisomer 2);

N- [6- (4-fluorophenyl) hexyl] - [4- (4-carboxymethyl) benzyl) sulfinyl-2-oxo-azetidin-1-yl] -acetamide (diasteroisomer 2); (47 R, SS / 4S, SR) -4- (Benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one;

(47 R, SS / 4S, SR) -4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one;

(4 R, SS / 4S, SR) -N- (6-Phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(4 R, SS / 4 S, SR) -N-Benzyl- (4-benzylsulfinyl-2-oxoazetidine-

1- yl) acetamide;

(47 R, SS / 4S, SR) -N- (9-Phenylnonyl) - (4-benzylsulfinyl-

2-oxoazetidin-1-yl) acetamide;

(47 R, SR / 4S, SS) -N-6- (4-Methoxyphenyl) hexyl- (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide;

(47 R, SS / 4 S, S 7 R) -N-6- (4-methoxyphenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(47 R, SS / 4 S, S 7 R) -N-6- (4-Chlorophenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(4 R, 4 S) -N-6- (4-Chloro-phenyl) -hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(47 R, SS / 4S, SR) -N-6- (3,5-Dichloro-phenyl) -hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(47 R, SS / 4 S, S 7 R) -N- (6- (3-Chlorophenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide;

(4R, SS / 4S, S7R) -N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzylsulphinyl-2-oxoazetidin-1-yl) acetamide;

N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulfony1-2oxoazetidin-yl) acetamide;

(47 R, SS / 4 S, S 7 R) -4- (Benzylsulfinyl) -1- (2-phenethyl-2-oxononyl) azetidin-2-one;

(35.4 R, 5 R) -N- (6-Phenylhexyl) - (4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl) acetamide;

(35.4 R, 5 R) -N- (6-Phenylhexyl) - (4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl) acetamide;

N- (6- [4-chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2);

N- (6- [4-chlorophenyl] hex-1-yl) - (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2).

Since the compounds of the invention, more particularly the compounds of formula (I), are intended for use in pharmaceutical compositions, it is clear that each of them is in substantially pure form, for example at least 50% pure, more preferably at least 75% pure. % purity and preferably at least 95% purity (% based on weight). Impure preparations of the compounds of formula (I) may be used to prepare purer forms useful in pharmaceutical compositions. Although the purity of the intermediates in the preparation of the compounds of formula (I) is less essential, it is clear that the pure forms of the intermediates are preferable, as in the case of compounds of formula (I). a.

If any of the compounds of the invention crystallize or recrystallize from organic solvents, the crystalline product may be present in the crystalline product. The present invention also includes such solvates. Some of the compounds of the present invention may similarly crystallize from the environment of solvents containing water. In such cases, hydrates may be formed. The present invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water. The latter compounds of varying water content can be prepared by methods such as lyophilization. In addition, crystallization conditions can lead to the formation of various polymorphic forms of crystalline products. The present invention includes within its scope all polymorphic forms of the compounds having formula (I).

The compounds of this invention are inhibitors of the lipoprotein associated phospholipase A ₂ (Lp-PLA ₂ ) enzyme and are expected to be useful in therapy, more particularly in the treatment of atherosclerosis. Therefore, the invention further provides a compound of formula (I) for use in therapy. Said compounds of formula (I) are inhibitors of Lp-PLA ₂ lysophosphatidylcholine production and therefore may be of general use in any disease caused by endothelial dysfunction, for example in atherosclerosis, diabetes, hypertension, angina and after ischemia and reperfusion. In addition, the compounds of formula (I) may be of general use in any disease in which lipid peroxidation is associated with an enzymatic action, for example, in addition to conditions such as atherosclerosis and diabetes, also in conditions of rheumatoid arthritis, defeat, brain inflammatory conditions such as , myocardial infarction, reperfusion cases, sepsis, acute and chronic inflammation. Other such conditions include various neuropsychological diseases such as schizophrenia (see Psychopharmacology Bull., 31, 159-165 (1995)).

Other uses include any disease associated with the activation of monocytes, macrophages or lymphocytes, since all these cell types express Lp-PLA ₂ . An example of such a disease is psoriasis.

Accordingly, the invention further provides a method of treating a disease state associated with the action of Lp-PLA ₂ , the method comprising treating a patient in need of such treatment with a therapeutically effective amount of an inhibitor of said enzyme. The disease state may be associated with an increased activity of monocytes, macrophages or lymphocytes, the formation of lysophosphatidylcholine and oxidized free fatty acids, lipid peroxidation in conjunction with the effect of Lp-PLA ₂ , or endothelial dysfunction.

The compounds of the present invention may also be used in the treatment of the above conditions in combination with antihyperlipidemic or anti-atherosclerotic or anti-blood sugar or anti-angina or anti-inflammatory or anti-hypertensive agents. Examples of the above

flow include cholesterol synthesis inhibitors such as statins, antioxidants such as probucol, insulin sensitizers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.

For therapeutic use, the compounds of this invention are usually administered in the form of a conventional pharmaceutical composition. The present invention therefore also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

Suitable pharmaceutical compositions include those compositions that are suitable for oral or parenteral administration, or as suppositories.

Compounds of formula (I) that are effective when administered orally may be formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules, and lozenges.

Liquid formulations generally comprise a suspension or solution of said compound or a pharmaceutically acceptable salt thereof in a suitable liquid carrier (s), for example ethanol, glycerol, non-aqueous solvents such as polyethylene glycol, oils, or water with dispersants; the composition may hopefully contain preservatives, flavors and colorings.

The composition in the form of tablets can be prepared using any of the pharmaceutical carrier (s) commonly used in the preparation of solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

The capsule composition can be prepared by conventional capsule preparation methods. For example, pellets containing the active ingredient can be prepared using conventional carriers and then filled into a hard gelatin capsule; alternatively, a suspension or dispersion may be prepared using any suitable pharmaceutical carrier (s), for example aqueous solutions of gums, celluloses, silicates or oils, and the dispersion or suspension is then filled into soft gelatin capsules.

Typical parenteral compositions comprise a solution or suspension of a compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration.

Typical suppository formulations comprise a compound of formula (I) that is effective in this mode of administration, with a binder and / or lubricant such as polymer glycols, gelatin or cocoa butter, or other low melting vegetable or synthetic waxes or fats.

Preferred is the composition in unit dosage form such as a tablet or capsule.

Each dosage unit for oral administration preferably contains from 1 to 500 mg (and for parenteral administration preferably contains from 0.1 to 25 mg) of a compound of formula (I).

For example, the daily dosage regimen of an adult patient may be between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, orally, intravenously, subcutaneously or intramuscularly, between 0.1 mg and 100 mg, preferably between 0.1 and 25 mg. mg of a compound of formula (I), wherein the compound is administered 1 to 4 times daily. Suitable compounds are administered for a period of continuous therapy, for example, for a week or longer.

Compounds of formula (I) may be prepared from suitable starting materials by adapting synthesis procedures well known in the art. Suitable methods include the reaction of azetidone of formula (II):

S (O) nR ³ (II) in which:

n, R ³ , R ² and R ³ are as defined above;

with an alkylating agent having the formula (III):

z-ch ₂ -xy wherein Z is a suitable exchangeable group such as halogen; and

X and Y are as defined above;

under suitable alkylation conditions.

Suitable alkylation conditions are well known to those skilled in the art and include the use of a suitable base such as sodium hydroxide or potassium hydroxide in a suitable alkylating solvent, for example tetrahydrofuran (THF) and at a temperature in the range of -10 to 0 ° C. The alkylation is usually conveniently carried out with compounds having the formula (II) in which n is 0.

Compounds having formula (I) wherein n is 1 or 2 can be easily prepared from compounds of formula (I) wherein n is 0 by reacting them with a suitable oxidizing agent such as m-chloroperoxybenzoic acid. Use of chiral oxidizing agents such as (+) - or (-) -1,1'-bi-2-naphthol / titanium isopropoxide (N. Komatsu et al., J. Org. Chem. 58: 7624-7626 (1993)) )) may provide diasteroisomeric selectivity if not chiral pure compounds.

The compounds of formula (II) wherein n is 0, may be obtained by reaction of 4-acetoxy azetidinone, 4-benzoyloxyazetidi _yl and methanone and 4-fenylsulfonylazetidinonu with a thiol R SH in the presence of a base such as sodium ethoxide, in a suitable solvent, such as ethanol, at a temperature in the range of 0 to 5 ° C. If this reaction is conducted in the presence of a chiral base such as quinchonidine or cinchonine, enantiomerically enriched compounds (II) can be obtained (Shibasaki et al., JCS Chem. Commun. 1883, 1324).

Compounds of formula (III) may be readily prepared by known methods of preparation, tailored to a certain X value. The usual starting material is an appropriately substituted aryl compound, which may be folded to carry the Z-CH ₂ X- side chain.

Compounds having formula (I) wherein X is CONR ³ (CH ₂ ) _m (amide) or CONHO (CH ₂ ) _m (hydroxamate) may conveniently be prepared by the action of an acid of formula (IV):

R ²

S (O) n R ³

CH-CO.H ⁴ t

wherein o 3 n, R ¹ , R and R are as defined above; with amine of formula (V):

NHR ⁵ (CH ₂ ) _m Y or with hydroxylamine of formula (VI):

^NH 2 ° ( ^CH 2) m ^Y

(V) (VI) wherein R ³ , Y and m are as defined above;

under suitable coupling conditions to form an amide or hydroxyamate.

Suitable conditions are known to those skilled in the art and include the use of an activator such as chloroformate or dicyclohexylcarbodiimide (DCC) in a suitable solvent such as chloroform or dimethylformamide at a temperature in the range of -10 to 20 ° C.

The acid of formula (IV) can be obtained by the action of a 2-bromoacetic acid ester on the compound of formula (II) under the alkylation conditions mentioned above. Subsequent hydrolysis of the resulting ester intermediate gives the acid of formula (IV).

The compounds of formula (I) wherein X is a group COO _(CH2) (ester) may be conveniently prepared by transesterification of the ester of formula (VII)

S (O) n R ³

N \

CH ₂ -CO ³ R ⁶

in which:

I ^{t R 6 (C} (I-6? ^-alkyl, n, R ^1, R ² and R ³ are as hereinbefore defined;

using conditions suitable for transesterification.

Suitable conditions are known to those skilled in the art and include, for example, heating in toluene in the presence of a catalytic amount of sodium methoxide and an alcohol. A suitable compound of formula (VII) is the methyl ester wherein r6 is methyl.

The compound of formula (VII) can be obtained by reacting the compound of formula (II) with the n-alkyl ester of 2-bromoacetic acid under conditions suitable for the alkylation described above.

Compounds of formula (VII) are novel compounds that are useful as intermediates for the preparation of compounds of formula (I).

Therefore, the invention further provides compounds of formula (VII) as defined herein.

Said compounds of formula (VII) are also Lp-PLA ₂ inhibitors and are therefore useful in the various diseases listed above for compounds of formula (I).

Compounds of formula (I) wherein X is C00 (CH ₂ ) _m (ester) may alternatively be prepared by reacting a compound of formula (IV) with an alcohol Y (CH ₂ ) _m OH, or activated derivatives thereof, for example tosylates.

In addition, compounds of formula (I) in which n is 0 may be prepared by a process comprising reacting a compound of formula (VIII):

in which R ¹ ,

R and R are the same as above;

with an alkylating agent of formula (IX):

R ³ Z (IX)

Q wherein R and Z are as defined above;

under suitable alkylation conditions, for example in a solvent such as acetonitrile at a temperature in the region of 25 ° C.

Compounds of formula (VIII) can be obtained from the corresponding 4-acetylazetidinones by reaction with silver nitrate and a base, in a suitable solvent such as methanol.

If desired, mixtures of diastereoisomeric compounds of formula (I) may be resolved by methods known in the art. For example, sulfoxides can be separated by chromatography and / or crystallization. Chiral-pure compounds can be prepared by chiral chromatography from chiral-pure intermediates or reagents, or by chiral synthesis using chiral catalysis. Suitable chiral intermediates can be obtained by repeated dissolution or chiral induction, or by using chiral reagents, in particular natural chiral molecules, by methods well known to those skilled in the art. For chiral synthesis, the usual starting material is a penicillin derivative having a preferred configuration on the C-4 β-lactam ring. This is explained in more detail below:

O ^Br , Ρ (Ο! Ρτ) ₃ .ΑγΟ J ý - N benzene q SAc \ (i) 0 ₃ . ElOAc. -70 "N ^ COO-pMS (ii) PiOMeJj ° COO-pMB X M acid

PbCHjBí

---- ►

MeCN

NEl ₃ . AgNO

MeOH

5-10

₃ ^ph mCPSA

------------>.

CONH (CH ₂ ), Ph (i)

DCC / HOBt ----- ►

Ph (CH _{2) 6} N H

O «SCH.Ph

CONH (CH), Ph

ΖλΆοΟΗ / CHjCIj

--► 5 ’

CONH (CH,), Ph

The preparation of the starting material (4-methoxybenzyl-6-bromenicenicinate-1-oxide) is described in J. Chem. Soc. Perkin Trans. 1, 179-188 (1994).

The present invention will be further elucidated by way of examples. In these examples, diastereoisomers of sulfoxides with R, R / S, S or R, S / S, R configurations are given. These configurations were first obtained from X-ray diffraction analysis of a limited number of compounds and then extrapolated to the remaining compounds based on their ³ H NMR spectra. Unless stated

otherwise, all compounds are racemic. Chiral compounds are described as 4S or S, SR or S, wherein 4 denotes the center of the C4 position in the azetidinone and S denotes the sulfoxide center. If mixtures of sulfoxides are obtained, spectra are given for both stereoisomers (50:50 mixtures) or for the major isomers (for example 90:10 mixtures). All compounds are characterized by NMR and most by microanalysis and mass spectrometry.

DETAILED DESCRIPTION OF THE INVENTION

Preparations

Preparation 1: 6- (4-methoxyphenyl) hexylamine

a) 6-Bromo-1- (4-methoxyphenylhexane)

A solution of 6-bromohexanoyl chloride (50 g, 0.2 mol) in dry dichloromethane (40 mL) was added dropwise over 5 minutes to a suspension of hin trichloride (31 g, 0.2 mol).

in dry dichloromethane (100 mL). The temperature was kept between 20 and 23 ° C. The mixture was stirred at room temperature for 30 minutes to give a yellow solution. Anisole (23 g, 0.2 mol) in dry dichloromethane (30 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. Triethylsilane (59.9 g, 0.515 mol) was then added over 10 minutes while maintaining the temperature between 25-35 ° C. The solution was stirred for 60 minutes at room temperature and then poured onto a mixture of ice and water (200 g). The organic layer was washed with brine and water until the pH of the solution was neutral. Drying (MgSO ₄ ) and evaporation under reduced pressure gave a yellow oil which was distilled under reduced pressure at 90-110 ° C / 0.5 mbar. Product containing fractions were combined and purified by flash chromatography on silica gel using hexane as eluent to give a colorless oil (18.33 g, 33%).

b) N- (4-Methoxybenzyl) -6-hexyl phthalimide

6-Bromo-1- (4-methoxyphenyl hexane) (26.5 g, 0.1 mole) was dissolved in DMF (140 mL), potassium phthalimide (36.2 g, 0.2 mole) was added and the mixture was was stirred for 18 hours at 100 ° C. The mixture was evaporated, the residue taken up in ether and excess potassium phthalimide was separated by filtration. The filtrate was washed with water, dried (MgS0 ₄₎ and evaporated to give a yellow solid which was recrystallised from ether / petroleum ether to give a light yellow solid (20.0 g, 61%), mp 63-65 ° C

c) 6- (4-Methoxyphenyl) hexylamine

N- (4-methoxybenzyl) -6-hexyl phthalimide (19.9 g, 60 mmol) was dissolved in ethanol (300 mL) and hydrazine monohydrate (8.9 g, 0.11 mol) was added. The mixture was heated at boiling for 3 hours, filtered, the residue washed with ethanol and the filtrate evaporated. The residue was taken up in diethyl ether, filtered and washed well with ether. Evaporation of the filtrate gave a yellow oil which was purified by distillation to give a clear oil, bp 108-110 ° C at 0.02 mbar.

Preparation 2: 6- (3,5-di-tert-Butyl-4-hydroxyphenyl) hexylamine This compound was prepared from 3,5-di-tert-butyl-4-hydroxyphenol according to the general procedure outlined in 1. preparation.

Preparation 3: 6- (3-Chlorophenyl) hexylamine

a) 6- (3-Chlorophenyl) hexin-1-ol

A mixture of 3-chloroiodobenzene (14.3 g, 60 mmol), tetrakis (triphenylphosphine) palladium (2.1 g, 1.8 mmol) and 5-hexin-1-ol (5.9 g, 60 mmol) in triethylamine ( 120 ml) was stirred for 3 hours at 25 ° C and then partitioned between water and ether. The ether layer was separated and the aqueous layer was extracted with ether. The combined ether extracts were washed with 1 M hydrochloric acid solution and dried (Na ₂ SO 4). The ether was evaporated and the residue was purified by flash chromatography on silica using dichloromethane as eluent. Evaporation of the appropriate fractions gave an oily product (11.5 g, 92%).

b) 1- (phthalimido) -6- (3-chlorophenyl) hex-1-yne

A solution of 6- (3-chlorophenyl) hexin-1-ol (11.5 g, 55 mmol), triphenylphosphine (14.5 g, 55 mmol) and phthalimide (8.1 g, 55 mmol) in dry THF (110 mL) ) was treated with a solution of DEAD (9.6 g, 55 mmol) in THF (20 mL) for several minutes. After 16 hours the volatiles were removed in vacuo and the residue was taken up in ether. The precipitated solid was removed, the filtrate was evaporated and the residue was purified by flash chromatography on silica using dichloromethane as eluent. Evaporation of the appropriate fractions gave the product as a solid (16.5 g, 89%).

c) 6- (3-Chlorophenyl) hexylamine

To a suspension of 1- (phthalimido) -6- (3-chlorophenyl) hex-1-yne

(10 g, 30 mmol) in methanol (100 mL) was added platinum oxide (250 mg), and the mixture was hydrogenated for 72 hours under 50 psi. Additional portions of catalyst were added successively, and when the theoretical weight gain was achieved, the mixture was filtered, the filtrate was evaporated until a brown oil (9.5 g, 96%) was obtained.

This material was dissolved in IMS 99 (100 mL) and treated with hydrazine hydrate (2.8 g, 56 mmol) for 16 hours at reflux. The mixture was cooled to 5 ° C and the precipitated solid was removed by filtration. Evaporation of the filtrate gave an oily substance which was taken up in ether, washed with water, dried (Na ₂ SO ₄ ) and evaporated to give a brown oil (5.8 g, 98%).

4. Preparation: 6- (3,5-Dichlorophenyl) hexylamine

This material was prepared by the method generally described in Preparation 3. The product was obtained as an oil.

Preparation 5: 4- (4- (Allyloxycarbonyl) benzylthio) azetidin-2-one

a) Allyl 4- (bromomethyl) benzoate

4- (Bromomethyl) benzoic acid (103 g, 0.48 mol) was suspended in thionyl chloride (200 mL) and 1 mL of dimethylformamide was added. The mixture was heated at reflux until clear, evaporated and azeotroped with toluene (2 x 150 mL). The resulting oil was dissolved in dichloromethane and added dropwise to a cooled solution of pyridine (42 mL) and allyl alcohol (40 mL) in dichloromethane. The mixture was stirred at room temperature for 1 hour, then washed with water, 2M hydrochloric acid solution, sodium bicarbonate solution and brine. The organic solutions were dried and evaporated to give allyl 4- (bromomethyl) benzoate as a light oil (98 g, 84%). ^X H-NMR δ (CDC1 ₃₎ 4.61 (2H, s', _CH2), 4.82 (2H, m, _CH2 O), 5.34 (2H, m, _CH2-CH-), 6, 05 (1 H, m, CHCH ₂ ),

7.45 (2H, d, Ph-H); 8.03 (2H, d, Ph-H).

b) Allyl 4- (acetylthiomethyl) benzoate

To a cooled suspension of potassium thioacetate (46 g, 0.4 mol) in dry dimethylformamide (200 mL) was added dropwise allyl 4- (bromomethyl) benzoate (98 g, 0.4 mol) in dry dimethylformamide (100 mL). The cooling bath was removed and the mixture was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate, (3x). The combined extracts were washed with water and brine. The mixture was dried and evaporated to give allyl 4- (acetylthiomethyl) benzoate as an orange oil (100 g, 100%).

^{Χ Η} NMR δ (CDC1 _3): 2.36 (3H, s, _COCH3), 4.13 (2H, s, _CH2),

4.82 (2H, m, CH ₂ O), 5.32 (2H, m, CH ₂ CH-), 6.05 (1H, m, CHCH ₂ ), 7.35 (2H, d, Ph-H) 7.98 (2H, d, Ph-H).

c) 4- (4- (Allyloxycarbonyl) benzylthio) azetidin-2-one

To a solution of potassium tert-butoxide (4.93 g, 0.044 mol) in dry tetrahydrofuran (100 mL) was added dropwise allyl alcohol (27 mL) in dry tetrahydrofuran (50 mL). After stirring for 5 minutes, a solution of allyl 4- (acetylthiomethyl) benzoate (10.1 g, 0.04 mol) in dry tetrahydrofuran (100 mL) was added dropwise. After stirring for 15 minutes, a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 mol) was added dropwise. The mixture was stirred for 1 hour and evaporated. The residue was partitioned between ethyl acetate and water, the aqueous phase was extracted again with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. Purification by flash chromatography (silica gel, ethyl acetate-petroleum ether) gave 4- (4- (allyloxycarbonyl) benzylthio) azetidin-2-one as an oil (9.1 g, 82%).

^X H-NMR δ (CDC1 _3): 2.84 (1H, dd, ₃ H), 4.31 (1H, dd, J _3b, H, 3.88 (2H, s, _S-CH2), 4.68 (1H, dd, H ₄ ), 4.78 (2H, m, CH ₂ O),

5.35 (2H, m, CH ₂ CH), 6.05 (1H, m, CH CH _2), 6.07 (1H, šir.singlet, NH), 7.40 (2H, d, Ph-H ), 8.03 (2H, d, Ph-H).

6. Preparation: 4- (4- (Allyloxycarbonylmethyl) -benzylthio) azetidin-2-one

a) Allyl 4- (bromomethyl) phenylacetate

The colorless oily material, yield 95% of theory, NMR δ ^X (CDC1 _3): 3.7 (2H, s), 4.5 (2H, s), 4.6 (2H, m),

5.25 (2H, m), 5.9 (1H, m), 7.15-7.4 (4H, dd).

b) Allyl 4- (acetylthiomethyl) phenylacetate

Colorless oil, 96% of theory. ¹ H NMR δ (CDCl ₃ ): 2.36 (3H, s), 3.6 (2H, s), 4.1 (2H, s),

4.65 (2H, m), 5.25 (2H, m), 5.9 (2H, m), 7.23 (4H, dd).

c) 4- (4- (Allyloxycarbonylmethyl) -benzylthio) -azetidin-2-one

Yellow oil, 69% yield.

^X H-NMR δ (CDC1 _3): 2.81 to 2.88 (1H, dd), 3.26 3.35 (lH, dd), 3.65 (2H, s), 3.83 (2H, s), 4.6 (2H, m), 4.68 (1H, dd), 5.20-5.32 (2H, m), 5.60 (1H, broad), 5.8-6.0 (1H, m), 7.21-7.31 (4H, dd).

References for the preparation of other amines:

6-phenylhexylamine: Morse M.A. et al., Cancer Research, 1846 (1991).

6- (4-chlorophenyl) hexylamine: Lamattina J. L. EP 138 464

A2 850,424 (CA 103: 142,000)

6- (4-hydroxyphenyl) hexylamine: Goodwin B. L. et al., Xenobiotica, 24, 129 (1994)

4-Acetoxyzetidin-2-one: Clauss K. et al., Annalen, 539 (1974)

Example 1

4- (benzylthio) -1- (4-phenyl-2-oxobutyl) azetidin-2-one

(a) 4- (Benzylthio) azetidin-2-one

Sodium (8.1 g, 0.35 mol) was dissolved in ethanol (250 mL) and benzyl mercaptan (45.2 g, 0.37 mol) was added dropwise over 20 minutes while maintaining the temperature at room temperature.

she asked between 20-25 ° C and bubbled through the reaction mixture nitrogen. Mon 15 minutes, the reaction mixture was cooled to 5 ° C and over The solution was added dropwise over 15 minutes

4-acetoxyazetidin-2-one (45.0 g, 0.35 mol) in ethanol (50 mL) and the temperature was still maintained at 5 ° C. The mixture was stirred at room temperature for 60 minutes and then evaporated to dryness under reduced pressure. Water (400 mL) was added, the mixture was extracted with dichloromethane (2 x 300 mL), the extracts were dried (MgSO ₄ ) and evaporated under reduced pressure to an oily consistency. The oil was cooled to -20 ° C and triturated with ether (400ml) to give a white solid which was collected by filtration (50.2g, 79%), mp 50-51 ° C .

^Δ NMR (CDCl ₃ ): 2.86 (1H, m, H _3a ), 3.30 (1H, m, H _3a ), 3.85 (2H, s, SCH ₂ ), 4.68 (1H , m, H ₄ ), 7.31 (5H, m, Ph-H).

b) 4- (Benzylthio) -1- (4-phenyl-2-oxobutyl) azetidin-2-one

To the chilled (bath

4- (benzylthio) azetidin-2-one tetra-n-butylammonium bromide with cold water) solution (5.5 g, 28.5 mmol), (0.9 g,

2.85 mmol) and 1-bromo-4-phenylbutan-2-one (7.1 g,

31.3 mmol) dry

THF (100 mL) was added freshly triturated potassium hydroxide (1.8 g, 31.3 mmol) and the mixture was stirred effectively for 2 h.

at ambient temperature. Water was then added and the product was extracted into ethyl acetate, dried (MgSO ₄ ) and evaporated to an oil. Treatment of the residue with ether gave the product as a white crystalline solid (3.12 g, 32%), mp 79-81 ° C.

^Δ NMR (CDCl ₃ ): 2.58 (2H, m CH ₂ CO), 2.86 (2H, t, J = 7.5Hz, CH ₂ Ph), 2.96 (1H, dd, J = 2.2 Hz, H _3a ), 3.17, 3.98 (each 1H, d, J = 18.5 Hz, NCH ₂ ), 3.43 (1H, dd, J = 5.1, 15, 2 Hz, H _3b ), 3.70 (2H, s, SCH ₂ ), 4.89 (1H, dd, J = 2.4, 5.1 Hz, H ₄ ), 7.15-7.33 ( 10H, m, Ph-H).

Determined composition: C 70.9%, H 6.3%, N 4.3%, C 20 H 21 O 2 requires: C 70.8%, H 6.2%, N 4.1%.

Example 2 (47 R, SR / 4S, S S) 4- (Benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one

4- (Benzylthio) -1- (4-phenyl-2-oxobutyl) azetidine solution

The 2-one (3.1 g, 9.2 mmol) in dichloromethane (100 mL) was cooled to -50 to -60 ° C and a solution of m-chloroperoxybenzoic acid (1, 1, 2) was added dropwise over 30 minutes with stirring. 9 g, 11 mmol) in dichloromethane (80 mL). The reaction mixture was maintained at said temperature of -50 to -60 ° C for an additional 30 minutes and then shaken with a mixture of saturated sodium sulfite solution and saturated

sodium bicarbonate solution, the organic layers were separated, dried (MgSO ₄ ) and evaporated to dryness. Recrystallization twice from ethyl acetate gave (4 R, S 7 R, 4 S, SS) 4- (benzylsulfinyl) 1- (4-phenyl-2-oxobutyl) azetidin-2-one (0.8 g, 27%). m.p. 147-149 ° C.

² H NMR δ (CDCl ₃ ): 2.71 (2H, m CH ₂ CO), 2.89 (2H, m, CH ₂ Ph), 2.93 (1H, dd, J = 4.7, 14, 8 Hz, H _3a ), 3.36 (1H, dd, J = 1.8,

14.8 Hz, H _3b ), 3.72, 4.37 (each 1H, d, J = 18.9 Hz, NCH ₂ ),

3.9 (2H, s, _CH2 SO), 4.70 (1H, - 7.40 (10H, m, Ph-H).

Determined composition: 67.5 (C 20 H 21 NO 3 S) requires: 67.6 dd, J = 2.2, 4.7 Hz, H ₄ ), 7.12% C, 6.0% H, 4.0% N,% C, 6.0% H, 3.9% N.

Example 3 (47 R, SS / 4S, SR) 4- (Benzylsulfinyl) -1- (4-phenyl)

2-Oxobutyl) azetidin-2-one The combined filtrates from lysis were evaporated and ethanol to recrystallize twice the above double crystal residue (predominantly (4 R, SS / 4 S, R?)).

4- (benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one (1.2 g, 37%), m.p.

111 ° C.

¹ H NMR δ (CDCl ₃ ): 2.45 (1H, dd, J = 2.3, 15.4 Hz, H _3a ), 2.71 (2H, m CH ₂ CO), 2.89 (2H, m, CH ₂ Ph), 3.03 (1H, dd, J = 5.1, 15.3 Hz, H _3b ), 3.94, 4.12 (each 1H, d, J = 13.0 Hz, CH ₂ SO 4, 4.19, 4.37 (each 1H, d, J = 19.2 Hz, NCH ₂ ), 4.65 (1H, dd,

J = 2.4, 5.1 Hz, H ₄ ), 7.12 - 7.40 (10H, m, Ph-H).

Determined composition: 67.5% C, 6.1% H, 4.1% N, ^C 20 ^H 21 ^NO 3 ^S requires: 67.6% C, 6.0% H, 3.9% N.

Example 4

4- (benzylsulfonyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

To a cold (ice bath) solution of 4- (benzylthio) -N (4-phenyl-2-oxobutyl) azetidinone (0.6 g, 1.9 mmol) in dichloromethane (25 mL) was added dropwise with stirring m-chloroperoxybenzoic acid (0.92 g, 5.3 mmol) in dichloromethane (25 mL). The ice bath was removed and after 1.5 hours the reaction solution was washed with a mixture of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfite solution. The aqueous layer was back extracted with dichloromethane and the combined organic layers were dried (MgSO ₄ ).

and evaporated until an oily residue was obtained which was crystallized from ether. The product 0.56 g is obtained, m.p. 131-133 ° C.

^Δ NMR (CDCl ₃ ): 2.69 (2H, t, J = 6.9 Hz, CH ₂ CO), 2.9 (2H, m, CH ₂ Ph), 2.94 (1H, dd, J = 2.4, 10.8 Hz, H _3a ), 3.14 (1H, dd, J = 5.1, 15.4 Hz, H _3b ), 3.82, 4.35 (each 1H, d J = 18.8 Hz, NCH ₂ ), 4.28 (2H, s, SO ₂ CH ₂ ), 4.89 (1H, dd, J = 2.3, 5.1 Hz, H ₄ ), 7 14-7.43 (10H, m, Ph-H).

Determined Composition: 64.5% C, 5.8% H, 3.8% N, ^C 20 ^H 21 ^NO 4 ^S requires: 64.7% C, 5.7% H, 3.8% N.

The following compounds (Examples 5 to 25) were prepared using the general preparation methods of the preceding Examples (Examples 1 to 4). Where indicated, the ratio means the relative proportion (4 R, S / R / 4S, SS: 4 R, SS / 4 S, S 7?) As determined by ³ H NMR.

Example 5

4- (Benzylthio) -1- (2-phenyl-2-oxoethyl) azetidin-2-one Colorless oil, 48% of theory.

NMR δ (CDCl ₃ ): 3.02 (1H, dd, J = 15.25, 2.00 Hz, H _3a ),

3.27 (1H, dd, J = 5.15, 15.25 Hz, H _3b ), 3.72 (1H, d,

J = 21.76, _COCH2), 3.75 (2H, s, _SCH2), 4.70 (1H, d, J = 18.3

Hz, COCH ₂ ), 5.08 (1H, dd, J = 2.39, 5.13 Hz, H ₄ ), 7.08-7.29 (5H, m, Ph-H), 7.44-7 7.50 (2H, m, Ph-H), 7.57-7.64 (1H, m, Ph-H), 7.76-7.80 (2H, m, Ph-H).

Example 6 (47 R, S 7 R, 4 S, SS) 4- (Benzylsulfinyl) -1- (2-phenyl-2-oxoethyl) azetidin-2-one

White solid, 11.5% of theory, mp 130-131 ° C.

Determined composition: C 65.8%, H 5.2%, N 4.4%, C 18 H 17 O 3 requires: C 66.0%, H 5.2%, N 4.3%.

Example 7 (47 R, SS / 4 S, S 7 R) 4- (Benzylsulfinyl) -1- (2-phenyl-2-oxoethyl) azetidin-2-one

White solid, diasteroisomer ratio 15:85, 15% of theory), m.p. 92-93 ° C.

Determined composition: C 65.8%, H 5.3%, N 4.4%, ^C 18 ^H 17 ^NO ₃ S requires: C 66.0%, H 5.2%, N 4.3%.

Example 8

4- (benzylthio) -1- (9-phenyl-2-oxononyl) azetidin-2-one

a) 1-Bromo-9-phenylnonan-2-one

To a suspension of aluminum chloride (31.0 g, 0.233 mol) in dry dichloromethane (100 mL), maintained at a temperature between 20 and 23 ° C, was added dropwise a solution of 6-bromohexanoyl chloride (49.7 g, 0.233 mol) over 5 minutes. ) in dry dichloromethane (40 mL). The mixture was stirred at room temperature for 30 minutes to give a yellow solution. A solution of benzene (18.2 g, 0.233 mol) in dry dichloromethane (30 mL) was added and the reaction mixture was stirred at room temperature for 20 hours. Triethylsilane (59.9 g, 0.515 moles) was then added over 10 minutes while maintaining the temperature between 25-35 ° C. The solution was stirred at room temperature for 60 minutes. It was then poured onto a mixture of ice and water (200 g). Partial separation occurred and the organic layer was washed with brine and then several times with water until the pH of the solution was neutral. The organic solution was dried (MgSO 4) and evaporated under reduced pressure to give a yellow oil. This was distilled under reduced pressure at 90 ° C / 0.5 mbar to give a colorless oil. The appropriate portions were combined and purified

flash chromatography on silica gel using hexane to give 6-bromo-1-phenylhexane as a colorless oil (18.33 g, 33%).

6-Bromo-1-phenylhexane (18.02 g, 0.075 mol) was dissolved in acetone (300 mL), sodium iodide (44.85 g, 0.299 mol) was added, and the mixture was heated at reflux for 18 hours. Then the mixture was filtered and the acetone was evaporated under reduced pressure to give a residue which was extracted with n-pentane (150 mL). The undissolved solid was filtered off and the filtrate was evaporated to give 6-iodo-1-phenylhexane as a colorless liquid (21.22 g, 99%).

Dissolve 6-iodo-1-phenylhexane (17.43 g, 0.061 mol), acetylacetone (6.66 g, 0.067 mol) and potassium carbonate (8.41 g, 0.061 mol) and absolute solution in absolute ethanol (75 mL). was refluxed for 18 hours. After cooling to room temperature, the solution was filtered and evaporated under reduced pressure to give an oily residue. The residue was partitioned between ethyl acetate (80 mL) and water (80 mL), the organic layer was washed with brine, dried and evaporated to give an orange oil (15.27 g). The oil was purified by flash chromatography on silica gel using petroleum ether / ethyl acetate to give 9-phenylnonan-2-one as a colorless oil (7.12 g, 54%).

To a solution of 9-phenylnonan-2-one (7.12 g, 0.033 mol) in dry methanol (75 mL) was added bromine (5.21 g, 0.033 mol) with stirring, and the solution was stirred at room temperature for 2 hours. Water (50 ml) was then added and stirring was continued for 18 hours at room temperature. Ether (175 mL) and water (100 mL) were added. The organic layer was then washed with dilute aqueous NaHCO 3 (2x), dried (MgSO ₄ ) and evaporated under reduced pressure to give an oily residue (5.39 g). Petroether (40 ° C to 60 ° C, 50 mL) was added and the mixture was cooled to -10 ° C and filtered. The obtained solid was redissolved in ether (40 mL) and evaporated under reduced pressure to an oily residue (4.06 g) which was further purified by flash chromatography on silica gel using hexane / ethyl acetate to give 1-bromo- 9-fenylnonan27

2-one as a light yellow solid (3.80 g, 39%).

b) 4- (Benzylthio) -1- (9-phenyl-2-oxononyl) azetidin-2-one theoretical yield.

(6H, m, (CH ₂ ) ₃ ), (2H, m, CH ₂ CO), (1H, dd, J = 15.2,

J = 18.6Hz, (2H, s,

Colorless oil, ¹ H NMR δ (CDCl ₃ ): CH ₂ CH ₂ Ph, J = 7.5

3.21 to

J = 5.1,

J = 2.4%

1.3

CH ₂ CH ₂ CO ₂ , 2.24 Hz, CH ₂ Ph),

2.97

4.01 (each 1H, d,

15.2 Hz, H _3b ), 3.73

5.1 Hz, H ₄ ), 7.14-7.35 (10H,

1.55 (4H,

2.60 (2H,

2.2Hz, m, t,

NCH ₂ ), 3.43 (1H, dd, SCH ₂ ), 4.93 (1H, dd, m, Ph-H).

Example (42 R, SR / 4S, SS) 4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one

Colorless solid, 25% of theory, mp 133-135 ° C.

^X H-NMR δ (CDC1 _3): 1.3 (6H, m, (CH _{2) 3),} 1.58 (4H, m,

CH ₂ CH ₂ Ph, CH ₂ CH ₂ CO, 2.37 (2H, t, J = 7.5 Hz, CH ₂ CO), 2.59 (2H, t, J = 7.9 Hz, CH ₂ Ph), 2.94 (1H, dd, J = 14.8, 4.7 Hz,

H _3a ), 3.36 (1H, dd, J = 1.7, 14.9 Hz, H _3b ), 3.79, 4.42 (1H, d, J = 18.9 Hz, NCH ₂ ), 3.91 (2H, s, SOCH ₂ ), 4.77 (1H, dd, J = 2.2, 4.7 Hz, H ₄ ), 7.15 to 7.4 (10H, m, Ph-H ).

Determined composition: 70.3% C, 7.2% H, 3.4% N, ^C 25 ^H 31 ^NO 3 ^S requires: 70.6% C, 7.3% H, 3.3% N.

Example 10 (42 R, S 5/45, S 2 R) 4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one

Diastereoisomer ratio 1: 9, colorless solid, 30% of theory, mp 75-76 ° C.

^X H-NMR δ (CDC1 _3): 1.3 (6H, m, (CH _{2) 3),} 1.58 (4H, m, CH ₂ CH ₂ Ph, CH ₂ CH ₂ O), 2.34 (2H , t, J = 7.6 Hz, _CH2 CO), 2.43 (1H, dd, J = 2.3, 15.2 Hz, 2.59, ₃ H), 2.59 ((2H, t , J =

7.4 Hz, CH ₂ Ph), 3.02 (1H, dd, J = 15.3, 5.1 Hz, ₃ H), 3.94,

4.13 (each 1H, d, J = 13.0 Hz, SOCH ₂ ), 4.19, 4.38 (each

1H, d, J = 18.7 Hz, NCH ₂ ), 4.65 (1H, dd, J = 2.4 and 5.1 Hz,

Η ₄ ), 7.14 to 7.43 (10 °, m, Ph-H).

Determined composition: 70.4% C, 7.3% H, 3.4% N, ^C 25 ^H 31 ^NO 3 S requires: 70.6% C, 7.3% H, 3.3% N.

Example 11

4- (2-Methoxybenzylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless solid, 62% of theory.

¹ H NMR δ (CDCl ₃ ): 2.60 (2H, m, CH ₂ CO), 2.87 (2H, t, J = 7.5 Hz, CH ₂ Ph), 3.01 (1H, dd, J = 15.2, 2.2 Hz, H _3a ), 3.23, 4.00 (each 1H, d, J = 18.6 Hz, NCH ₂ ), 3.43 (1H, dd, J = 15 2.5 (5.1 Hz, H _3b ), 3.72 (2H, d, J = 2.4 Hz, SCH ₂ ), 3.83 (3H, s, OCH ₃ ), 4.95 (1H, dd) J = 2.4 5.1 Hz, H ₄ ), 6.81-6.92 (2H, m, 3,5- (2-CH ₃ OPh) -H), 7.15-7.32 ( 7H, m,

4,6- (2-CH ₃ OPh) -H, Ph-H).

Example 12 (4R, SR / 4S, SS) 4- (2-Methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, 8% of theory, mp 90-92 ° C.

¹ H NMR δ (CDCl ₃ ): 2.71 (2H, m, CH ₂ CO), 2.88 (2H, m, CH ₂ Ph), 3.00 (1H, dd, J = 14.8, 4 7 Hz, H _3a ), 3.46 (1H, dd, J =

11.9 14.8 Hz, H _3b ), 3.70, 4.35 (each 1H, d, J = 18.4,

NCH ₂ ), 3.88 (3H, s, OCH ₃ ), 4.00 (2H, s, SCH ₂ ) 4.75 (1H, dd,

J = 2.2 4.7 Hz, H ₄ ), 6.90-7.38 (9H, m, Ph-H + CH ₃ OPh-H).

Assay Composition: 65.3% C, 6.0% H, 3.9% N, C21H23NO4S requires -: 65.4% C, 6.0% H, 3.6% N.

Example 13 (4R, SS / 4S, SR) 4- (2-Methoxybenzylsulphinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil, diastereoisomeric ratio 1: 3, 25% of theoretical. ¹ H NMR δ (CDCl ₃ ): 2.49 (1H, dd, J = 2.2 15.4 Hz, H _3a ), 2.71 (2H, m, CH ₂ CO, 2.89 (2H, m, CH ₂ Ph), 3.04 (1H, dd, J =

15.4, 5.1 Hz, H _3b ), 3.87 (3H, s, 0%), 4.09 (2H, s, SCH ₂ )

4.19, 4.36 (each 1H, d, J = 18.6 Hz, NCH ₂ ), 4.69 (1H, dd,

J = 2.3, 5.0 Hz, H ₄ ), 6.89 to 7.34 (9H, m, Ph-H + CH ₃ OPh-H).

Determined: C 64.8%, H 6.1%, N 3.8%,

C21H23NO4S. 0.17 _H2O requires C 64.9%, H 6.1%, 3, 6% Ni

Example 14

4- (4-fluorobenzylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil, 41% of theoretical yield.

¹ H NMR δ (CDCl ₃ ): 2.640 (2H,

7.5 Hz, CH ₂ Ph), 2.95 (1H, d 4.06 (each 1H, d, J = 18.6 15.3, 5.1 Hz, H _3B), 3.67 (2H

2.4 5.1 Hz, H ₂ O, 6.84-7.33 m, CH ₂ CO), 2.887 (2H, t, J =

J = 15.3. 2.3 Hz, H _3a ), 3.3, Hz, nch ₂ ), 3.42 (1 H, dd, J = with, sch ₂ ), 4.88 (1 H, dd, J =

(9H, m, Ph - H, 4 - Ph - H).

Example 15 (47 R, 5 S / 4 S, SS) 4- (4-Fluorobenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, 16% of theory, mp 152-154 ° C.

^Δ NMR (CDCl ₃ ): 2.74 (2H, t, J = 7.0 Hz, CH ₂ CO), 2.90 (2H, t, J = 6.8 Hz, CH ₂ Ph), 2 95 (1H, dd, J = 14.8, 4.7 Hz,

H _3a ), 3.35 (1H, dd, J = 1.8 14.8 Hz, H _3b ), 3.76, 4.40 (each 1H, d, J = 18.9 Hz, NCH ₂ ), 3.85 (2H, m, _SCH2), 4.73 (1H, dd, J = 2.2, 4.7 Hz, H _4), 7.04 to 7.32 (9H, m, Ph-H, 4-FPh-H).

Assay Composition: 64.2% C, 5.4% H, 3.9% N, 620-420-438 requires: 64.3% C, 5.4% H, 3.8% N.

Example 16 (47 R, SS / 4 S, ST R) 4- (4-Fluorobenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, 26% of theory.

¹ H NMR δ (CDCl ₃ ): 2.60 (1H, dd, J = 2.3, 15.2 Hz, H _3a ),

2.71 (2H. M, _CH2 C0), 2.91 (2H. M, _CH2 Ph), 3.15 (1H, dd,

J = 5.1, 15.2 Hz, H _3b ), 3.96 (2H, m, SCH ₂ ), 4.19, 4.38 (each 1H, d, J = 18.7 Hz, NCH ₂ ) 4.65 (1H, dd, J = 2.4, 5.1 Hz, H ₄ ), 7.05-7.33 (9H, m, Ph-H, 4-FPh-H).

Specified composition:

^ 20 ^ 20 ^ θ3 ^ requires:

64.1% C, 5.5% H, 3.9% N,

64.3% C, 5.4% H, 3.8% N.

Example 17

4- (4-Methoxybenzyltio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystals, 74% yield, mp 70-71 ° C.

^Δ NMR (CDCl ₃ ): 2.60 (1H, t, J = 7.13Hz, CH ₂ Ph), 2.86 (1H, t, J = 7.59Hz, COCH ₂ ), 2.96 (1H, dd, J = 15.25, 2.20 Hz, H _3a ), 3.24 (1H, d, J = 18.53 Hz, NCH ₂ ), 3.42 (1H, dd, J = 15.25, 5, 11 Hz, H _3b ), 3.66 (2H, s, SCH ₂ ), 3.76 (3H, s, OCH ₃ ), 4.02 (1H, d, J = 18.53 Hz, NCH ₂ ), 4.88 (1H, dd, J = 5.10, 2.39 Hz, H ₄ ), 6.79-6.84 (2H, m, Ph-H), 7.16-7

7.32 (7H, m, Ph - H).

Example 18 (4R, SR / 4S, SS) 4- (4-Methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, 20% yield, mp 155-157 ° C.

Determined composition: 64.5% C, 6.0% H, 3.5% N, ^C 21 ^H 23 ^NO 4 ^S · ⁰ ' ^{3 H} 2 ° requires: 64.5% C, 6.1% H, 3 , 6% N.

Example 19 (47 R, SS / 4 S, S 7 R) 4- (4-Methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline substance. 80% of said diastereoisomer, mp 92-93 ° C, 31% yield.

Determined composition: 64.7% C, 6.0% H, 3.5% N,

C21H23NO4S.0,2 H ₂ 0 requires: C 64.8%, H 6.1%, N 3.6%

Example 20

4- (phenethylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil, yield 80% of theory.

³ H NMR δ (CDCl ₃ ): 2.65-2.97 (9H, m, S-CH ₂ CH ₂ , COCH ₂ CH ₂ , H _3a ), 3.39 (1H, dd, J = 15.22 5.00 Hz, H _3b ), 3.50 and 4.17 (each 1H, d, J = 18.48 Hz, N-CH ₂ ), 4.83 (1H, dd, J = 4.99, 2, 34 Hz, H ₄ ), 7.14-7.33 (10H, m, Ph-H). _;

Example 21 (42 R, 7 R, 4 S, SS) 4- (Phenethylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline material, yield 8% of theory, melting point 163-165 ° C

Determined composition: 68.0% C, 6.2% H, 4.0% N, ^C 21 ^H 23 ^NO 3 ^S requires: 68.3% C, 6.3% H, 3.8% N.

Example 22 (47 R, SS / 4 S, S 7 R) 4- (Phenethylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline material, yield 14.5% of theory, melting point 91-92 C.

Determined composition: 68.08% C, 6.32% H, 3.86% N, ^C 21 ^H 23 ^NO 3 ^S requires: 68.3% C, 6.3% H, 3.8% N.

Example 23

4- (3-Phenylpropylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil, yield 67%.

³ H NMR δ (CDCl ₃ ): 1.87 (2H, m, SCH ₂ CH ₂ ), 2.47 (2H, m, CH ₂ CO), 2.72 (4H, m, -2x CH ₂ Ph) , 2.9 (2H, t, J = 7.1 Hz, _CH2 S), 2.96 (1H, dd, J = 2.2, 15.2 Hz, ₃ H), 3.48 (1H, dd, J = 5.0, 15.2 Hz, H _3b ), 3.63, 4.23 (each 1H, d, J = 18.5 Hz, NCH ₂ ), 4.86 (1H, dd, J = 2.3, 5.0 Hz, H ₄ ),

7.14-7.32 (10H, m, Ph-H).

Example 24 (47 R, 5 S / 4 S, SS) 4- (3-Phenylpropylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, yield 25% of theory, mp 136-138 ° C ¹ H NMR δ (CDC1 _3): 2.11 (2H, m, S0CH _{2 CH2),} 2.49 (2H, m,

SOCH ₂ ), 2.78 (4H, m, 2 x CH ₂ Ph), 2.91 (2H, m, CH ₂ CO), 3.15 (1H, dd, J = 4.8, 14.7 Hz, H _3a ), 3.55 (1H, dd, J = 1.7,

14.7 Hz, H _3b ), 3.78, 4.44 (each 1H, d, J = 18.9 Hz, NCH ₂ ),

4.66 (1H, dd, J = 2.2, 4.8 Hz, H ₄ ), 7.14-7.35 (10H, m, Ph-H).

Determined composition: 68.6% C, 6.4% H, 3.8% N, 22.225, 25% requires: 68.9% C, 6.6%, 3.7% N.

Example 25.

(4 R, SS / 4 S, SR) 4- (3-Phenylpropylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, yield 13% of theory, melting point 65-60 ^° C

NMR δ (CDCl ₃ ): 2.12 (2H, m, SOCH ₂ CH ₂ ), 2.54 (2H, m,

SOCH ₂ ), 2.55 to 2.94 (7H, m, 2 x CH ₂ Ph + CH ₂ CO + H _3a ), 3.33 (1H, dd, J = 5.2, 15.1 Hz, H _3b ), 4.20, 4.40 (each 1H, d, J = 18.7 Hz; NCH ₂ ), 4.66 (1H, dd, J = 2.2, 4.8 Hz, H ₄ ),

7.14-7.35 (10H, m, Ph-H).

Determined composition: 68.6% C, 6.5% H, 3.9% N, 22.225, 25.3% requires: 68.9% C, 6.6% H, 3.7% N.

Example 26 trans-3-Methyl-4- (benzylthio) -1- (4-phenyl-2-oxobutyl) azetidin-2-one

A solution of trans-3-methyl-4- (benzylthio) azetidi-2-one (0.73 g, 3.5 mmol) with dry THF (5 mL) was added dropwise to a suspension of sodium hydride (60%) over 5 min. suspension in oil (0.15 g, 3.8 mmol) in dry THF (10 mL) under a nitrogen atmosphere at -10 ° C. After the addition, the mixture was stirred at -10 ° C for 10 minutes, and 1-bromo-4-phenylbutan-2-one (0.79 g,

3.5 mmol) in dry THF (10 mL). The mixture was then stirred at room temperature for 30 minutes and then poured into ice-water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ) and evaporated to an oily residue. The residue was purified by flash chromatography on silica gel using petroleum ether (40-60 ° C) / ethyl acetate 3: 1, 2: 1 to give a colorless solid (0.34 g,% yield, mp 69-71 ° C). C.

^X H-NMR δ (CDC1 _3): 1.34 (3H, d, J = 7 Hz, _SCH3), 2.55 (2H, m, _CH2 Ph), 2.85 (2H, t, J = 8 0 Hz, COCH ₂ CH ₂ ), 3.11, 3.97 (each 1H, d, J = 18 Hz, NCH ₂ ), 3.15 (1H, m, H ₃ ), 3.70 (2H, m, SCH ₂ , 4.50 (1H, d, J = 2 Hz, H ₄ ), 7.1-7.4 (10H, m, 2 x Ph-H).

Example 27 (47 R, S 7 R, 4 S, SS) trans -3-Methyl-4- (benzylsulfinyl) -

1- (4-Phenyl-2-oxobutyl) azetidin-2-one

Prepared from trans-3-methyl-4- (benzylthio) -1- (4-phenyl-

2-Oxobutyl) azetidin-2-one according to the general preparation method of Example 2. A white solid was obtained, 40% of theory, m.p. 87-94 ° C. ^X H-NMR δ (CDC1 _3): 1.23 (3H, d, J = 7 Hz, _CH3), 2.71 (2H, m, _CH2 Ph), 2.90 (3H, m, COCH ₂ + H ₃ ), 3.91, 4.09 (each 1H, d,

J = 13 Hz, SOCH ₂ ), 4.17, 4.39 (each 1H, d, J = 19 Hz,

NCH ₂ ), 4.38 (1H, d, J = 2 Hz, H ₄ ), 7.1-7.4 (10H, m,

Ph-H).

Determined composition: 68.1% C, 6.3% H, 4.0% N, ^C 21 ^H 23 ^NO 3 ^S requires: 68.3% C, 6.3% H, 3.8% N.

Example 28 (4R, SS / 45, S7R) trans -3-Methyl-4- (benzylsulfinyl) -

1- (4-Phenyl-2-oxobutyl) azetidin-2-one

Prepared from trans-3-methyl-4- (benzylthio) -1- (4-phenyl-

2-oxobutyl) -azetidin-2-one according to the general method of preparation described in Example 2a.

^X H-NMR δ (CDC1 _3): 1.43 (3H, d, J = 8 Hz, _CH3), 2.7 (2H, m,

CH ₂ Ph), 2.9 (2H, m, COCH ₂ ), 3.65, 4.37 (each 1H, d, J = 19

Hz, NCH ₂ ), 3.82 (1H, m, H ₃ ), 3.93 (2H, m, SOCH ₂ ), 4.44 (1H, d, J = 2 Hz, H ₄ ), 7.1 to 7.4 (10H, m, Ph-H).

Determined composition: 68.1% C, 6.3% H, 4.0% N,

C21H23NO3S requires: 68.3% C, 6.3% H, 3.8% N.

Example 29

N- (6phenylhexyl) - (4-benzylthio-2-oxoazetidin1-yl) acetamide

a) Methyl (4-benzylthio-2-oxoazetidin-1-yl) acetate

To a solution of 4- (benzylthio) azetidin-2-one (5.0 g, mmol), methyl bromoacetate (4.6 g, 30 mmol) and tetrabutylammonium bromide (0.9 g, 0.29 mmol) in dry THF (150 g) triturated potassium hydroxide (1.7 g, 30 mmol) was added. The resulting mixture was stirred for two hours at room temperature. Then water (50 ml) was added. The solution was extracted with ethyl acetate (3 x 150 mL portions) and the combined extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel using petroleum ether (60-80 ^° C): ethyl acetate 4: 1 to give methyl (4-benzylthio-2-oxoazetidin-1-yl) acetate as a yellow oil ( 5 g, 70% of theory).

^X H-NMR δ (CDC1 _3): 2.96 (1H, dd, J = 16, 2.5 Hz, ₃ H), 3.24,

3.99 (each 1H, d, J = 18.00 Hz, NCH ₂ ), 3.4 (1H, dd, J = 5,

12.5 Hz, H _3b ), 3.70 (3H, s, OCH ₃ ), 3.77 (2H, s, SCH ₂ ), 4.92 (1H, m, H ₄ ), 7.28 (5H) , m, Ph-H).

(b) Methyl- (4-benzylthio-2-oxoazetidin-1-yl) acetic acid

To a solution of methyl (4-benzylthio-2-oxoazetidin-1-yl) acetate (2.5 g, 9.4 mmol) in methanol (80 mL) was added 1 M sodium hydroxide solution dropwise at 0 ° C. (9.9 ml,

9.9 mmol). The reaction mixture was stirred for 1 hour and evaporated to dryness. Water (50 ml) was added, the solution was acidified to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate (3 x 100 ml). The combined extracts were dried (MgSO ₄ ), evaporated and the residue purified by recrystallization (hexane / ether) to give methyl- (4-benzylthio-2-oxoazetidin-1-yl) acetic acid as white

solid (1.3 g, 55%), mp 110-111 ° C.

³ H NMR δ (CDCl ₃ ): 2.99 (1H, dd, J = 17.5, 6.87 Hz, H _3a ),

3.27, 4.06 (each 1H, d, J = 18.40 Hz, NCH ₂ ), 3.39 (1H, dd, J = 5, 15.4 Hz, H _3b ), 3.77 ( 2H, s, _SCH2), 4.91 (1 H, m, H _4);

7.27 (5 H, m, Ph-H).

c) N- (6-Phenylhexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide To DDC (8.2 g, 40 mmol), hydroxybenztriazole (5.3 g, 39 mmol) and acid (4) benzylthio-2-oxoazetidin

1-yl) acetic acid (10 g, 39 mmol) was added a solution of 6-phenylhexylamine (Morse MA et al., Cancer Research 1846 (1991)) and stirred for 2 hours at room temperature. Ethyl acetate (250 mL) was added, the precipitate was filtered off, the filtrate was washed with dilute NaHCO ₃ solution, water (2x), dried (MgSO ₄ ) and evaporated to an oily residue which was purified by flash chromatography on silica gel using hexane. ethyl acetate (1: 1). Evaporation of the appropriate fractions followed by treatment with hexane gave a white solid (11.2 g, 70%), mp 65-70 ° C.

Example 30 (42 R, 5 S / 4 S, SS) N- (6-Phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

A solution of N- (6-phenylhexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide (18 g, 43.8 mmol) in dichloromethane (500 mL) was cooled to -70 ° C and dropwise over A solution of m-chloroperoxybenzoic acid (6.7 g, 43.8 mmol) was added with stirring for 60 minutes. in dichloromethane (500 mL). After an additional three hours at -60 ° C, the reaction mixture was shaken with a mixture of saturated aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated to dryness. The solid residue was triturated with ether and filtered off. Recrystallization twice from ethyl acetate gave N- (6-phenylhexyl) (4-benzylsulfinyl-2-oxo-azetidin-1-yl) acetamide (3.8 g, 20%) m.p. 138-140 ° C.

Determined composition: 67.4% C, 6.9% H, 6.8% N, 24.24, 30.22, 3.12 requires: 67.6% C, 7.1% H, 6.6% N.

Example 31 (4R, SS / 4S, SS) N- (6-Phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

The filtrate from the previous example was diluted with hexane, filtered, and standing to give the title compound as a colorless crystalline solid (4.5 g, 24%), mp 107-108 ° C.

Assay Composition: 67.4% C, 7.1% H, 6.8% N, C 24 H 30 N 2 O 3 S requires: 67.6% C, 7.1% H, 6.6% N.

The following compounds (Examples 32-57) were prepared using the general preparation methods of Examples 29-5

31. Where the diasteroisomer ratio is reported, this ratio means the proportions (41µ, SR / 4S, SS: 47µ, SS / 4S, SR) as determined by NMR.

Example 32

N-benzyl- (4-benzylthio-2-oxo-azetidin-l-yl) acetamide

White solid, 49% yield, mp ¹ H NMR δ (CDCl 3): 2.94

3.37 (1H, dd, J = 2.5, 5 J = 15 Hz, NCH ₂ ), 3.76

4.81 (1H, m, H ₄ ), 6.33-90 ° C.

(1H, dd, J = 2.5, 5.25Hz, _H3a ),

Hz, H _3b ), 3.65, 3.76 (each 1H, d, (2H, s, SCH ₂ ), 4.4 (2H, m, NHCH ₂ ), (1H, broad s, NH), 7 20-7.37 (10H, m, Ph-H).

Example 33 (4R, SR / 4S, SS) N-Benzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White crystalline solid, yield 8% of theory, mp 192-193 ° C.

Assay Composition: 63.8% C, 5.7% H, 8.0% N, 19%, 20%, 20% requires: 64.0% C, 5.7% H, 7.9% N.

Example 34 (47 R, SS / 4 S, S 7 R) N-Benzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White crystalline solid, diasteroisomeric ratio 15:86, yield 36% of theory, mp 181-182 ° C.

Determined composition: 63.4% C, 5.5% H, 7.7% N, ^ 19 ^ 20 ^ 2θ3 ^ '^ 2θ requires: 63.5% C, 5.7% H, 7.8% N .

Example 35

N- (4-phenylbutyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide

Colorless oil, 100% yield.

^X H-NMR δ (CDC1 _3): 1.5 to 1.7 (4H, m, _{CH2 CH2),} 2.63 (2H, t, _CH2 Ph), 2.93 (1H, dd, J = 2.15 Hz, H ₃ ), 3.26 (2H, m,

NCH ₂ ), 3.36 (1H, dd, J = 5.15 Hz, H ₃ ), 3.53, 3.70 (each

1 H, d, J = 17 Hz, _NCH2), 3.79 (2H, s, _SCH2), 4.80 (1H, m,

H, 6.07 (1H, broad s, NH), 7.1-7.4 (10H, m, Ph-H).

Example 36 (47 R, 7 R, 4 S, SS) N- (4-Phenylbutyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White solid, 4: 1 diastereoisomeric yield, 15% yield, mp 161-162 ° C. ^{Χ Η} NMR δ (CDC1 _3): 1.5 to 1.7 (4H, m, _{CH2 CH2),} 2.62 (2H, t, J = 7 Hz, _CH2 Ph), 2.95 (1 H δ d, J = 5, 15 Hz, H ₃ ), 3.26 (2H, m, NHCH ₂ ), 3.45 (1H, dd, J = 2.15 Hz, H ₃ ), 3.71.4 10 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.88, 4.04 (each 1H, d,

J = 13 Hz S0CH _2), 4.51 (1 H, m, H ₄ ), 6.65 (1 H, wide s NH) 7.4 (10 H, m, 2xPh-H). Specified composition: 66.2% C, 6.5 % H, 7.0% N, ^C 22 ^H 26 ^N 2 ° 3 ^N requires : 66.3% C, 6.6 % H, 7.0% N.

Example 37 (47 R, S 5/45, S 7 R) N- (4-Phenylbutyl) -4- (benzylsulphinyl-2-oxoazetidin-1-yl) acetamide

White solid, diastereomeric ratio 5:95, 30% yield, mp 107-108 ° C. ^{Χ Η} NMR δ (CDC1 _3): 1.5 to 1.7 (4H, m, _{CH2 CH2),} 2.63 (2H, t, J = 7 Hz, _CH2 Ph), 2.85 (1 H , dd, J = 5, 15 Hz, ₃ H), 3.15 (1H, dd, J = 5, 15 Hz, ₃ H), 3.3 (2H, m, NH CH _2), 3.97, 4 15 (each 1H, d, J = 13 Hz, SOCH ₂ ), 4.60 (1H, m, H ₄ ), 7.1 to 7.1

7.4 (11H, m, 2xPh-H + NH).

Designed for: C 66.1%, H 6.5%, N 7.1%, C 22 H 26 N 2 O 3 requires: C 66.3%, H 6.6%, N 7.0%.

Example 38

N- (9-Phenylnonyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide

Colorless oil, 84% yield.

^X H-NMR δ (CDC1 _3): 1.28 to 1.48 (14H, m, 7xCH _2), 2.59 (2H, t, J = 7.7 Hz, Ph-H _2), 2.92, 2, 98 (1H, dd, J = 2.5, 15.4Hz,

H ₃ ), 3.2 (2H, m, NHCH ₂ ), 3.34, 3.40 (1H, dd J = 5.2, 15.4

Hz, H ₃ ), 3.56, 3.72 (each 1H, d, J = 16.8 Hz, NHCH ₂ ), 3.81 (2H, s, SCH ₂ ), 4.81 (1H, m, H ₄ ), 6.0 (1H, m, NH), 7.2 (10H, m, 2xPh-H).

Example 39 (4R, 4R, 4S, SS) N- (9-Phenylbutyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide

White solid, diastereoisomeric ratio 4: 1, 8% yield, mp 124-128 ° C. ¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (14H, m, 7xCH ₂ ), 2.59 (2H, t, J = 7Hz, CH ₂ Ph), 2.93,2, 97 (1H, dd, J = 4.8, 14.8 Hz, H ₃ ), 3.23 (2H, m, NHCH ₂ ), 3.44, 3.48 (1H, dd, J = 2, 14.8 Hz, H ₃ ), 3.7, 4.1 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 3.9,

4.13 (each 1H, d, J = 12.8 Hz, SOCH ₂ ), 4.5 (1H, m, H ₄ ), 6.59 (1H, s, NH), 7.16-7.41 (10H, m, 2xPh-H).

Determined composition: 68.9% C, 7.5% H, 5.6% N, ^C 27 ^H 36 ^N 2 ° 3 ^S requires: 69.2% C, 7.7% H, 6.0% N.

Example 40 (4R, SS / 4S, SS) N- (9-Phenylbutyl) - (4-benzylsulphinyl-2-oxoazolin-1-yl) acetamide

White solid, 4: 6 diastereoisomeric yield, 48% yield, mp 123-128 ° C. Δη NMR δ (CDCl ₃ ): 1.2 to 1.7 (14H, m, 7xCH ₂ ), 2.59 (2H, t, J = 7.8 Hz, CH ₂ Ph), 2.85 to 2, 97 (1H, m, H ₃ ), 3.1 to 3.5 (3H, m, NHCH ₂ , H ₃ ), 3.7 to 4.2 (4H, m, SOCH ₂ , NCH ₂ ), 5 to 4.6 (1H, 2xm, H ₄ ), 6.68 (1H, m NH), 7.17-7.42 (10H, m, 2xPh-H).

Found: 69.3% C, 7.8% H, 6.1% N, ^C 27 ^H 36 ^N 2 ° 3 ^S requires: 69.2% C, 7.7% H, 6.0% N.

Example 41

N-methyl-N- (6-phenylhexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide

Yellow oil, yield 88% of theory.

^{Χ Η} NMR δ (DMSO-350K): 1.25 to 1.57 (8H, m, 4xCH _2), 2.55 (2H, m, Ph-H _2), 2.79 2.95 (4H, m NCH ₃ ), 3.1 to 3.3 (2H, m, NCH ₂ ), 3.32, 3.35 (1H, dd, J = 5.2, 14.8 Hz, H ₃ ), 3, 45.

4.09 (each 1H, d, J = 16.8 Hz, NHCH ₂ C = O), 3.84 (2H, s,

SCH ₂ ), 4.94 (1H, m, H ₄ ), 7.14-7.32 (10H, m, 2xPh-H).

Example 42 (47 R, 7 R / 4S, SS) N-Methyl-N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless oil, diastereoisomeric ratio 55:45, yield 67% of theory.

^X H-NMR δ (DMSO-d ₆ 350K): 1.2 to 1.6 (8H, m, 4xCH _2), 2.56 (2H, t, J = 7.6 Hz, CH ₂ Ph) 2, 86 (4H, m, NCH ₃ ), 3.02-8

3.26 (m, H ₃ , NCH ₂ ), 3.81-4.4 (4H, m, SOCH ₂ , NCH ₂ C = O),

4.81, 4.90 (1H, 2xm, H ₄ ), 7.12-7.35 (10H, m, 2xPh-H).

Determined composition: C 65.4%, H 6.9%, N 6.3%, C 25 H 32 O 2 O 3 requires: C 68.1%, H 7.3%, N 6.4%.

Example 43 (47 R, SS / 4 S, S 7 R) N-Methyl-N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless oil, 13% yield.

¹ H NMR δ (DMSO-d ₆ 350K): 1.2 to 1.6 (8H, m, 4xCH ₂ ), 2.56 (2H, t, J = 7.6 Hz, CH ₂ Ph), 2, 86 (4H, m, NCH ₃ ), 3.1-3.3 (m, H ₃ , NCH ₂ ), 4.01 (2H, m, SOÔCH, NCHC = O), 4.17 (1H, d, 1 J = 12.9 Hz, S (CH), 4.37 (2H, d · J = 17.4 Hz, NCHC = O), 4.81 (1H, m, H ₄ ), 7.13 to 7, 35 (10H, m, 2.times.Ph-H).

Determined Composition: C 65.3%, H 6.8%, N 6.1%, ^C 25 ^H 32 ^N 2 ° 3 ^S requires C 68.1%, H 7.3%, N 6.4%.

Example 44

N- [6- (3,5-di-tert-butyl-4-hydroxyphenyl) hexyl] - (4-benzyltio2-oxo-azetidin-l-yl) acetamide

Yellow oil, yield 83% of theory.

^X H-NMR δ (CDC1 _3): 1.3 to 1.6 (26H, m, 4xCH ₂ + 6xCH _3), 2.50 (2H, t, J = 8 Hz, _CH2 Ph), 2.95 ( 1H, dd, J = 2, 15 Hz, ₃ H);

3.25 (2H, q, J = 7 Hz, NH CH _2), 3.37 (1H, dd, J = 5.1 Hz, ₃ H), 3.55, 3.71 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.82 (2H, s, SCH ₂ ), 4.80 (1H, m, H ₄ ), 5.03 (1H, s, OH), 6.02 1H, broad s , NH), 6.96 (2H, s, HOPh-H), 7.3 (5H, m, Ph-H).

Example 45 (4R, 5S / 4S, SR) N- [6- (3,5-Di-tert-Butyl-4-hydroxy-phenyl) -hexyl] - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Light brown glassy, yield 33% of theory.

^X H-NMR δ (CDC1 _3): 1.3 to 1.7 (26H, m, 4xCH ₂ + 6xCH _3), 2.50 (2H, t, J = 8 Hz, _CH2 Ph), 2.88 ( 1H, dd, J = 2, 15 Hz, ₃ H);

3.17 (1H, dd, J = 5.15 Hz, H ₃ ), 3.3 (2H, m, NHCH ₂ ), 3.89,

4.25 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.99, 4.19 (each 1H, d, J = 13 Hz, SOCH ₂ ), 4.61 (1H, m, H ₄ 5.02 (1H, s, OH),

6.96 (2H, s, HOPh-H), 7.25 (1H, broad s, NH), 7.3-7.5. (5H, m, Ph - H).

, The composition: 68.9% C, 8.3% H, 5.0% N,? 32 ^H 46 ^N 2 ° 4 ^S requires: 69.3% C, 8.4% H, 5.0% N.

Example 46

N-6- (4-methoxyphenyl) hexyl] - (4-benzylthio-2-oxoazetidin1-yl) acetamide

Yellow oil, yield 77% of theory.

^{Χ Η} NMR δ (CDC1 _3): 1.3 to 1.6 (8H, m, 4xCH _2), 2.54 (2H, t,

J = 15 Hz, CH ₂ PhOCH ₃ ), 2.95 (1H, dd, J = 2, 15 Hz, ₃ H); 3.23 (2H, m, NHCH ₂ ), 3.37 (TH, dd, J = 5, 15 Hz, H ₃ ), 3.55, 3.71 (every 1 H, d, J = 17 Hz, NCH ₂ ), 3.78 (3H, s, OCH ₃ ), 3.81 (2H, s, SCH ₂ ), 4.80 (1 H, m, H ₄ ), 6.01 (1 H, wide with, NH), 6.82, 7.07 (each 2H, d, J = 8.5) Hz, ch ₃ OPh-H), 7.3 (5H, m, Ph-H)

Example 47 (47 R, SR / 4S, SS) N- 6- (4-Methoxyphenyl) hexyl] - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White solid, 10% yield, mp 129-133 ° C.

¹ H NMR δ (CDCl ₃ ): 1.25 to 1.56 (8H, m, 4xCH ₂ ), 2.52 (2H, t, J = 7.25 Hz, CH ₂ Ph-O Me), 2.94 (1H, dd, J = 14.75, 4.5 Hz, H _3b ), 3.20 (2H, m, NHCH ₂ ), 3.45, (1H, dd, J = 2.0, 14.75) Hz,

H _3a ), 3.71, 4.23 (2H, dd, J = 15.5, 15.5 Hz, SOCH ₂ Ph), 3.78 (3H, s, OCH ₃ ), 3.88, 4, O 4 (2H, dd, J = 13.0, 12.75 Hz, N-CH ₂ ) 4.53 (1H, m, H ₄ ), 6.66 (1H, s, NH), 6.78-6 , 83,

7.06 to 7.09 (2H, 2H, m, _CH2 -Ph-0me), 7.22 to 7.26, 7.36 to 7.40 (3H, 2H, m, _2-Ph S0CH).

Determined composition: 64.9% C, 6.6% H, 6.1% N, ^C 25 ^H 32 ^N 2 ° 4 ^S requires: 65.8% C, 7.1% H, 6.1% N.

Example 48 (47 R, SS / 4 S, S 7 R) N- 6- (4-Methoxyphenyl) hexyl] - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Pale yellow solid, 29% yield, mp 85-88 ° C.

¹ H NMR δ (CDCl ₃ ): 1.23-1.63 (8H, m, 4xCH ₂ ), 2.53 (2H, t, J = 7.25 Hz, CH ₂ Ph), 2.88, ( 1H, dd, J = 15.25, 2.5 Hz, ₃ H), 3.13 to 3.3 (3H, m, NH CH _2), 3.78 (3H, s, .OCH ₃₎ 3, 85 to 4.28 (4H, m, NCH ₂ , SOCH ₂ Ph) 4.61 (1H, m, H ₄ ), 6.78 to

6.84, 7.05 7.10 (2H, 2H, m, _CH2-Ph-OMe), 7.18 (1H, s, CONH), 7.23 to 7.27, 7.37 to 7 44 (3H, 2H, m, SOCH ₂ Ph).

Designed for: 65.5% C, 6.8% H, 6.0% N, 25%, 32%, 32% requires: 65.8%, 7.1%, 6.1% N.

Example 49

N- (6- (4-chlorophenyl) hexyl] - (4-benzylthio-2-oxoazetidin-yl) acetamide

Light yellow solid, 89% yield, mp 60-62 ° C.

¹ H NMR δ (CDCl ₃ ): 1.3-1.6 (8H, m, 4xCH ₂ ), 2.55 (2H, t,

J = 7.6 Hz, _CH2 Ph), 2.90, 2.97 (1 H, dd, J = 2.4, 15.4 Hz,

H ₃ ), 3.3 (2H, m, NHCH ₂ ), 3.33, 3.40 (1H, dd, J = 5.2, 15.4 Hz, H ₃ ), 3.56, 3.71 (each 1H, d, J = 16.8 Hz, NCH ₂ ), 3.81 (2H, s, SCH ₂ ), 4.81 (1H, m, H ₄ ), 6.05 (1H, m, NH ), 7.05 to

7.36 (9H, m, 2.times.Ph-H).

Example 50 (4R, SR / 4S, SS) N- (6- (4-Chloro-phenyl) -hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, 17% yield, mp 178-179 ° C, ¹ H NMR δ (CDCl ₃ ): 1.2-1.6 (8H, m. 4xCH ₂ ), 2.55 (2H, m.p. t,

J = 7.6 Hz, PhCH ₂ ), 2.93, 2.99 (1H, dd, J = 4.7, 14.8 Hz),

H ₃ ), 3.22 (2H, m, NHCH ₂ ), 3.44, 3.49 (1H, dd, J = 2.2, 14.8

Hz, H ₃ ), 3.68, 4.13 (each 1H, d, J = 17.4 Hz, NCH ₂ ), 3.87, 4.05 (each 1H, d, J = 13.2 Hz, SOCH ₂ ), 4.50 (1H, m, H ₄ ),

6.65 (1H, m, NH), 7.07-7.40 (9H, m, 2xPh-H).

Determined Composition: C 62.5%, H 6.3%, N 6.3%, ^C 24 ^H 29 ^ClN 2 ° 3 ^S requires: C 62.5%, H 6.3%, 6.1% N.

Example 51 (4R, SS / 4S, R) N- (6- (4-Chlorophenyl) hexyl) (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, diastereomeric ratio 1: 9. Yield 39% of theory, melting point 103-104 ° C.

¹ H NMR δ (CDCl ₃ ): 1.3 to 1.6 (8H, m, 4xCH ₂ ), 2.56 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.87, 2, 90 (1H, dd, J = 2.5, 15.3 Hz, H ₃ ), 3.16, 3.20 (each 1H, d, J = 5.3, 15.3 Hz, H ₃ ), 3 26 (2Η, m, NHCH ₂ ), 3.87, 4.25 (each 1H, d, J = 17.2 Hz,

_NCH2), 3.98, 4.19 (each 1H, d, J = 13 Hz, _SOCH2), 4.6 (1H, m, H _$), 7.07 to 7.41 (10H, m, 2xPh-H, NH).

Assay Composition: 62.5% C, 6.3% H, 6.2% N, C 24 H 29 ClN 2 O 3 S requires: 62.5% C, 6.3% H, 6.1% N.

Example 52

N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin1-yl) acetamide

Light yellow oil, 69% yield.

^X H-NMR δ (CDC1 _3): 1.30 and 1.60 (m, 4xCH _2), 2.57 (2H, t,

J = 7.63 Hz, ArCH ₂ ), 2.95 (1H, dd, J = 2.4, 15.4 Hz, H _3a ), 3.24 (1H, m, NHCH ₂ ), 3.38 ( 1H, dd, J = 5.13, 15.4 Hz, H _3b ), 3.64 (2H, dd, J = 16.8 Hz, COCH ₂ N), 3.81 (2H, s, ArCH ₂ S) ), 4.81 (1H, m, J = 2.5 Hz, 5.0 Hz, ₄ H), 6.0 (1H, m, NHC = O), 7.0 7.36 (9H, m 9xArH).

Example 53 (47 R, 5 S / 4 S, SS) N- (6- (3,5-Dichlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White solid, 36: 1 diastereoisomeric yield, 37% yield, mp 158-159 ° C.

Determined composition: 58.2% C, 5.7% H, 5.7% N, ^C 24 ^H 28 ^Cl 2 ^N 2 ° 3 ^S requires: 58.2% C, 5.7% H, 5.7% N.

Example 54 (47 R, SS / 4 S, S 7 R) N- (6- (3,5-Dichlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White solid, 1: 9 diastereoisomeric yield, 22% yield, mp 108-109 ° C.

Assay Composition: 58.2% C, 5.6% H, 5.7% N, 24.28, 28.22, 203. Requires: 58.2% C, 5.7% H, 5.7% N.

Example 55

N- (6- (3-Chlorophenyl) hexyl) - (4-benzylthio-2-oxo-azetidin-l-yl)

-acetamide

Light yellow oil, 75% yield.

² H NMR δ (CDCl ₃ ): 1.30 to 1.60 (8H, m, 4xCH ₂ ), 2.55 (2H, t, J = 7.63 Hz, ArCH ₂ ), 2.95 (1H, dd, J = 2.5, 15.5 Hz, H _3a ), 3.24 (2H, m, J = 17.5 Hz, NHCH ₂ ), 3.38 (1H, dd, J = 5.25,

15.25 Hz, H _3b ), 3.64 (2H, dd, J = 16.87 Hz, COCH ₂ N), 3.82 (2H, s, ArCH ₂ S), 4.81 (1H, m, ₄ H), 6.06 (1 H, m, NH), 7.0

7.36 (8H, m, 8 * ArH).

Example 56 (47 R, 7 R, 4 S, SS) N- (6- (3-Chloro-phenyl) -hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) -acetamide White solid, diastreomeric ratio 36: 1, m.p. 147-148 ° C.

Determined Composition: C 62.3%, H 6.1%, N 6.2%, ^C ₂₄ ^H 29 ^ClN 2 ⁰ 3 ^S requires: C 62.5%, H 6.3%, N 6.1%.

Example 57 (47 R, SS / 4 S, S 7 R) N- (6- (3-Chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

White solid, diastereomeric ratio 14:86, yield 49%, mp 74-75 ° C.

Determined Composition: 62.4% C, 6.2% H, 6.1% N, ^C 24 ^H 29 ^ClN 2 ° 3 ^S requires: 62.5% C, 6.3% H, 6.1% N.

Example 58

N-6- (4-Hydroxyphenyl) hexyl- (4-benzylthio-2-oxoazetidin-1-yl) acetamide

Yellow oil. ¹ H NMR δ (CDCl ₃ ): 1.2 to J = 15 Hz, CH ₂ PhOH), 2.95 (2H, m, NHCH ₂ ), 3.37 (1H, (each 1H, d, J = 17) Hz, (1H, m, H ₄ ), 5.37 (1H, s

6.75, 7.02 (each 2H, d, J Ph-H).

yield 23% of theoretical yield

1.7 (8H, m, 4xCH _2), 2.52 (2H, t, (1 H, dd, J = 2.15 Hz, H ₃ ) 3.21 dd, J = 5.15 Hz, H ₃ ), 3.53, 3.72 nch ₂ ) , 3.76 (2H, s, _SCH2); 4.83 , OH) , 5.97 (1H, broad s, NH),

= 8.5 Hz, HOPh-H), 7.3 (5H, m,

Example 59 (47 R, S 7 R / 4S, SS) and (47 R, SS / 4 S, S 7 R) N-6- (4-Hydroxyphenyl) -hexyl- (4-benzylsulfinyl-2-oxoazetidine-1-) yl) acetamide

White glass, di-stereoisomeric ratio 1: 2, yield 79% of theory, melting point 38-49 ° C.

¹ H NMR δ (CDCl ₃ ): 1.25-1.58 (16H, m, 2xCH ₂ CH ₂ CH ₂ CH ₂ ),

2.52 (4H, t, J = 7.0 Hz, 2 x CH ₂ Ph), 2.83 (1H, dd, J = 15.0,

2.0 Hz, H _3a ), 2.90 (1H, dd, J = 15.0, 5.0 Hz, H _3b ), 3.12 to

3.25 (5H, m, 2xNHCH ₂ - H _3B), 3.40 (1H, dd, J = 15.0, 2.5 Hz,

H _3a ), 3.72-4.21 (8H, m, 2xSOCH ₂ Ph, 2xN-CH ₂ ), 4.56 (1H, m, H ₄ ), 4.64 (1H, m, H ₄ ), 6.08 (1H, s, OH), 6.17 (1H, s, OH),

6.63 (1H, m, NH), 6.71 to 6.77, 6.97 to 7.04 (4H, 5H, m, 2 x CH ₂ 0H-Ph, NH), 7.22 to 7.29 7.35 to 7.39 (4H, 6H, m,

2xSCH ₂ Ph).

Found: C 63.47, H 6.53, N 6.24, C 24 H 30 N 2 O 4 S requires: C 65.13, H 6.83, N 6.33.

Example 60

N- (6phenylhexyl) - (4- (4-ethoxycarbonyl) benzylthio-2-oxo-azetidin-l-yl) acetamide

a) 4- (4- (Ethoxycarbonyl) benzylthio) azetidin-2-one

Yield: 62% of theory.

¹ H NMR δ (CDCl ₃ ): 1.40 (3H, t, J = 7.13 Hz, O-CH ₂ CH ₃ ), 2.85 (1H, dd, unspecified, H _3a ), 3.31 (1H, dd, unspecified, H _3b ), 3.88 (2H, s, S-CH ₂ ), 4.38 (2H, q, J = 7.13 Hz, O-CH ₂ CH ₃ ), 6 10 (1H, broad singlet, NH), 7.40 (2H, d, J = 8.36Hz, Ph-H), 8.01 (2H, d, J = 8.34Hz, Ph-H) .

b) N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzylthio-2-oxoazetidin-1-yl) acetamide

Colorless oil, yield 59% of theory.

¹ H NMR δ (CDCl ₃ ): 1.23-1.71 (13H, m, CH ₂ CH ₂ , OCH ₂ CH ₃ ),

2.56 to 2.62 (2H, m, PhCH ₂ ), 2.93 (1H, dd, unspecified binding, H _3a ), 3.18 to 3.27 (2H, m, NH-CH ₂ ), 3 38 (1H, dd,

J = 15.37, 5.14 Hz, H _3b ), 3.52 and 3.80 (1H each, d, J =

16.64 Hz, N-CH ₂ ), 4.37 (2H, q, J = 7.13 Hz, O-CH ₂ CH 3), 4.85 (1H, dd, unspecified binding, H ₄ ), 6, 01 (1H, broad triplet,

N-H), 7.14-7.29 (5H, m, Ph-H), 7.39 (2H, d, J = 8.34; Hz,

Ph-H), 8.00 (2H, d, J = 8.30Hz, Ph-H).

- 4Š -

Example 61 (47 R, SS / 4 S, S 7 R) N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) -benzylsulphinyl-2-oxoazetidin-1-yl) acetamide

White crystalline solid, yield 25% of theory, melting point 101-103 ° C.

Found:% C, 64.69;% H, 6.64;% N, 5.72;% N, ^C 27 ^H 34 ^N 2 ^O 5 ^S requires% C: 65.04;% H; 6.87;

Example 62

N- (6phenylhexyl) -4- (4-chlorobenzylthio) -2-oxoazetidin-yl) acetamide

(a) 4- (4-Chlorobenzylthio) azetidinone

Crystalline solid, 72% yield, mp 73-74 ° C.

³ H NMR δ (CDCl ₃ ): 2.86 (1H, m, H _3a ), 3.32 (1H, m, H _3b ),

3.81 (2H, s, _S-CH2), 4.68 (1H, dd, J = 5.07, 2.46 Hz, ₄ H);

6.04 (1H, broad singlet, N-H), 7.24-7.33 (4H, m, Ph-H).

b) N- (6-Phenylhex-1-yl) -4- (4-chlorobenzylthio) -2-oxoazetidin-1-yl acetamide

Colorless oil, extract. ³ H NMR δ (CDCl ₃ ): 1.28-1.35 (2H, m, CH ₂ ), 1.53-1.60 Ph = CH ₂ , 2.92 (1H, (2H, dt, 4) line, Hz, H _3b ), 3.54 and 3.78 (2H, s, S-CH ₂ ), 4.83 (1H, s,

2.43 Hz, H ₄ ), 7.14-7.30 (9H, m, Ph-H).

1.51 t, J = 7.65 Hz,

H _3a ), 3.23

15.36, 5.16

Hz, N-CH _2), (4 H, m, _{CH2 CH2),} 1.40 (2H, dd,

NH-CH ₂ ), m, CH ₂ ), 2.60 (2H,

J = 15.37, 2.40 Hz,

3.38 (1 H, dd, J =

3.82 (1H each, d, J = 16.65 dd, J = 5.15,

Example 63 (47 R, SR / 4S, SS) N- (6-Phenylhex-1-yl) -4- (4-chlorobenzylsulphinyl) -2-oxoazetidin-1-yl acetamide

White crystalline solid, m.p. 155-156 ° C. Yield: 10% of theory.

Assay: 62.2% C, 6.2% H, 6.1% N,

C24H29ClN2O3S requires: C 62.5%, H 6.3%, N 6.1%.

Example 64 (47 R, SS / 4 S, S 7 R) N- (6-Phenylhex-1-yl) -4- (4-chlorobenzylsulfinyl) -2-oxazetidin-1-yl acetamide

Melting point 92 DEG-93 DEG C. Yield: 33%.

Assay Composition: 62.4% C, 6.3% H, 6.1% N, C 24 H 29 ClN 2 O 3 S requires: 62.5% C, 6.3% H, 6.1% N.

Example 65 trans N- (6-Phenylhexyl) - (4-benzylthio-3-methyl-2-oxoazetidin-1-yl) acetamide

Colorless oil, 65% yield.

^T H NMR δ (CDC1 _3): 1.2 to 1.7 (11H, m, 4xCH ₂ + CH _3), 2.59 (2H, t, J = 7 Hz, C H Ph), 3.2 ( 3H, m, NHCH ₂ + H ₃ ), 3.50, 3.70 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.80 (2H, s, SCH ₂ ), 4.42 (1H d, J = 2 Hz, H ₄ ), 6.04 (1H, broad s, NH), 7.1-7.4 (10H, m, 2xPh-H).

Example 66 trans N- (6-Phenylhexyl) - (4-benzylsulphinyl-3-methyl-oxoazetidin-1-yl) acetamide

White semi-solid, diastereomeric ratio 4: 6, yield 85% of theory.

^{Χ Η} NMR δ (CDC1 _3): 1.1 to 1.7 (11H, m, 4xCH ₂ + CH _3), 2.59 (2H, m, _CH2 Ph), 3.25 (2.6H, m , NHCH ₂ + H ₃ ), 3.7-4.3 (3.4H, m,

SOCH ₂ + H ₄ + H ₃ ), 6.65 (0.6H, broad s, NH), 7.1-7.4 (10.4H, m, 2xPh-H + NH).

Determined composition: 67.2% C, 7.3% H, 6.0% N, ^ 25 ^Η 32 ^ 2θ3 ^ requires:

68.2% C, 7.3% H, 6.4% N.

The following compounds (Examples 67-69) were prepared by oxidation of the corresponding sulfides described above using the general preparation method of Example 4.

Example 67

N- (6-Phenylhexyl) - (4-benzylsulphonyl-2-oxoazetidin-1-yl) acetamide |

White solid, 65% yield, mp 104-105 ° C.

, The composition: 64.7% C, 6.6% H, 6.3% N, ^C 24 ^H 30 ^N 4 ^S 2 ° ^{wherein the back} I ^t:

H, 6.8; N, 6.3.

Example 68

N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulfonyl-2-oxo-azetidin-l-yl) acetamide.

White solid, 90% yield, mp 115-116 ° C.

Determined composition: 55.2% C, 5.4% H, 5.4% N, ^ 24 ^ 28 ^^ 2 ^ 2θ4 ^ · θ'H ₂ 0 requires:

H, 5.6; N, 5.4.

Example 69

N- (6- (3-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide

White solid, yield 3% of theory, melting point 95-98 ° C.

Determined: 61.0% C, 6.2% H, 6.0% N,

C ₂₄ H ₂ qClN ₂ O ₄ S.0.12 C ₈ H ₄ requires:

H, 6.3; N, 5.8.

Example 70

4- (benzylthio) -1- (3-phenylpropyl) azetidin-2-one

A solution of 4- (benzylthio) azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10 mL) was added dropwise to a suspension of sodium hydride (0.13 g, 5.6) over 10 min. mmol)

in dry THF (5 mL) at -20 ° C under nitrogen. Then, a solution of 3-phenyl-1- (trifluoromethanesulfonyloxy) propane (1.5 g, 5.6 mmol) in dry THF (10 mL) was added dropwise at -55 ° C over 10 minutes. After stirring for 1 hour, the reaction mixture was poured onto ice-water (50 g), filtered through hyflo, THF was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The solution was washed (2x) with brine, dried (MgSO ₄ ), evaporated under reduced pressure, and purified by flash chromatography on silica gel using 5: 1 petroleum ether / ethyl acetate as eluent to give the title compound as a yellow oil. (1.4 g, 85% yield).

^Δ NMR (CDCl ₃ ): 2.58 (2H, m, CH ₂ ), 2.58 (2H, t, J = 15Hz, CH ₂ Ph), 2.9, 3.2 (each 2H, m , H-3 & _NCH2), 3.73 (2H, s, _SCH2), 4.51 (1H, m, H-4), 7.2 (10H, m, 2xPh-H).

Example 71 (4R, SR / 4S, S5) 4-Benzylsulfinyl-1- (3-phenylpropyl) azetidin-2-one

The compound was prepared from (4-benzylthio -) - 1- (3-phenylpropyl) azetidin-2-one using the general method of Example 2. The product was obtained as a white solid, diastereoisomeric ratio 97: 3, yield 19%. m.p. 93-96 ° C.

² H NMR δ (CDCl ₃ ): 1.83-1.94 (2H, m, CH ₂ CH ₂ CH ₂ ), 2.57-

2.69 (2H, m, _CH2 Ph), 2.76 (1H, dd, J = 14.5, 4.5 Hz, H _{3 b),}

3.22 to 3.39 (3H, m, _{N-CH2-H 3),} 3.83, 3.98 (2H, d, J =

13.0, 13.0 Hz, _SOCH2 Ph), 4.22 (1H, m, H _4), 7.13 to 7.41 (10H, m, CH ₂ Ph, Ph S0CH _2).

Determined Composition: C 69.5%, H 6.5%, N 4.5%, ^C 19 ^H 21 ^NO 2 ^S requires: C 69.7%, H 6.5%, N 4.3%.

Example 72 (47 R, SS / 4S, SR) 4-Benzylsulfinyl-1- (3-phenylpropyl) azetidine

- 2-one

The mother liquor from the above crystallization was reprocessed to give the title compound as a pale green oil with a 80:20 diastereomeric ratio, 14% yield.

^{Χ Η} NMR δ (CDC1 _3): 1.90 to 2.04 (2H, m, _{CH2 CH2 CH2),} 2.41 (1H, dd, J = 15.0, 2.4 Hz, ₃ H ), 2.59 to 2.64 (2H, m, _CH2 Ph), 2.84 (1H, dd, J = 15.0, 5.0 Hz, H _{3 b),} 3.41 to 3.49 ( 2H, m, N-CH2), 3.94 to 4.05 (2H, dd, J = 13.0, 13.0 Hz, ₂ SOC 2 Ph), 4.23 to 4.26 (1 H, m, H ₄ ), 7.15-7.39 (10H, m, SOCH ₂ Ph, CH ₂ Ph).

Determined composition: C 66.0%, H 6.4%, N 3.3%, C 19 H 21 N 2 O requires: C 69.7%, H 6.5%, N 4.3%.

The following compounds (Examples 73-75) were prepared using the general procedures of Examples 70-72.

Example 73

4-benzylthio-l- (2-phenethyl) azetidin-2-one

Pale brown oil, yield 60% of theory.

¹ H NMR δ (CDCl ₃ ): 2.8 to 2.9 (3H, m, CH ₂ Ph + H ₃ ), 3.1, 3.5 (each 1H, m, NCH ₂ ), 3.18 ( 1H, dd, J = 5.15 Hz, ₃ H), 3.66 (2H, dd, J = 14 Hz, _SCH2), 4.35 (1 H, m, H _4), 7.1 to 7, 4 (10H, m, 2xPh-H).

Example 74 (4R, SR / 4S, SS) 4-Benzylsulfinyl-1- (2-phenethyl) azetidin-2-one Colorless solid, 16% yield, mp 98-101 ° C.

¹ H NMR δ (CDCl ₃ ): 2.71 (1H, dd, J = 2.15 Hz, H ₃ ), 2.88 (2H, t, J = 7 Hz, CH ₂ Ph), 3.29 ( 1H, dd, J = 2.15Hz, H ₃ ), 3.3 (1H, m, NCH ₂ ), 3.7-3.9 (3H, m, NCH ₂ + SOCH ₂ ), 3.9 ( 1H, m,

H ₄ ), 7.1-7.4 (10H, m, Ph-H).

Determined composition: 68.7% C, 6.1% H, 4.5% N, C 18 H 18 NO 2 S requires: 69.0% C, 6.1% H, 4.5% N.

Example 75 (4R, SS / 4S, SR) 4-Benzylsulfinyl-1- (2-phenethyl) azetidin-2-one

Colorless solid, yield 27% of theory, yield: 51%, mp 88-89 ° C.

^X H-NMR δ (CDC1 _3): 2.40 (1 H, dd, J = 2, 15 Hz, ₃ H); 2.85 (1 H, d, 5.15 Hz, ₃ H); 3.0 (2H [, m, i ch ₂ ch ₂ Ph), 3.62, 3.76 (each 1H, m, NCH ₂ ), 3, 97, 4.03 (every 1 H; d, SÔCH ₂ ), 4.16 (1H, m, H ₄ ), 7.2-7.4 (10H, m, Ph-H). Determined composition : 68.8% C, 6.2 % H, 4.7% N, CisHigN0 ₂ S requires: 69.0% C, 6.1 % H, 4,5% N.

Example 76

4- (benzylthio) -1- (4-phenylbutyl) azetidin-2-one

To a suspension of NaH (0.123 g, 5.6 mmol) in dry THF (5 mL) at -20 ° C under a nitrogen atmosphere was added dropwise a solution of 4- (benzylthio) azetidin-2-one (1, 1, 3, 2 g, 5.5 mmol). A solution of 1-iodo-4-phenylbutane in dry THF (10 mL) was then added dropwise over 10 minutes at -55 ° C. The mixture was stirred for 18 hours, then evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with brine (2x), dried (MgSO ₄ ), evaporated under reduced pressure to a yellow oily residue which was chromatographed on silica gel eluting with 5: 1, 3: 1 and finally 1: 1 petroleum ether / acetate. ethyl acetate to give the product as a yellow oil (0.25 g, 14%).

^X H-NMR δ (CDC1 _3): 1.5 (4H, m, 2 x CH _2), 2.6 (2H, m, _CH2 Ph), 2.85, 3.2 (each 2H, m, H _3, and NCH ₂ ), 3.73 (2H, s, SCH ₂ ), 4.54 (1H, m, H ₄ ), 7.2 (10H, m, 2xPh-H).

Example 77 (47 R, SS / 4 S, S 7 R) 4-Benzylsulfinyl-1- (4-phenylbutyl) azetidin-2-one

Prepared from 4- (benzylthio) -1- (4-phenylbutyl) azetidin-2-one by the general procedure of Example 30. After purification by flash chromatography, the product was obtained as a yellow oil in a yield of 76% of theory.

^X H-NMR δ (CDC1 _3): 1.63 to 1.66 (8H, m, 2 x CH ₂ CH ₂ CH ₂ CH _2),

2.47 (1H, dd, J = 15.0, 1.50 Hz, H _3a ), 2.60 (4H, m, 2xCH ₂ Ph), 2.83 (1H, dd, J = 14.5, 4.5 Hz, H _3b ), 2.93 (1H,

dd, J = 15.0, 5.0 Hz, H _3b ), 3.29 until 3.50 (5H, m. 2xN-CH ₂ , H _3a ), 3.98, 4.06 (2H, dd, J = 13.25, 13.25 Hz, SOCH ₂ Ph), 3.83, 3.93 (2 H, dd, J = 6.25. 6. 25 Hz, SOCH ₂ Ph) 4.28 (1H, m, H ₄ ), 4.31 (1H, m, H) 4), 7 ,: 12-7.39 (20H, m. 2xCH ₂ Ph, 2xSCH ₂ Ph). Determined composition : 69.2% C, 6.9% H, 4.5% N, C ₂ qH ₂₃ NO ₂ S requires : 70.2% C, 6.8% H, 4,1% N.

Example 78 p-Methoxybenzyl [(3S, 4R) -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] acetate

a) p-Methoxybenzyl [(3S, 4S) -4-acetylthio-3-bromo-2-oxoazetidine-

1-yl] acetate

P-Methoxybenzyl-2 - [(3S, 4S) -4-acetylthio-3-bromo-

2-oxoazetidin-1-yl] -3-methylbut-2-enoate (Osborn N.F. et al., J. Chem. Soc., Perkin Trans. 1, 179 (1994)) (20.16 g,

Ozone air was bubbled through at -65 ° C to -70 ° C (0.0467 mol) in ethyl acetate (400 mL) until a permanent blue coloring of the solution was achieved. Excess ozone was removed by bubbling oxygen and then trimethyl phosphite (53.8 mL, 0.456 mol) was added dropwise. After 15 minutes, the solution was allowed to warm to room temperature and allowed to stand for 16 hours. Then the solvents were evaporated and the residue was diluted again and evaporated twice with toluene. The residue was then dissolved in ethyl acetate (300 mL), a solution of p-toluenesulfonic acid (2 g) in water (100 mL) was added, and the mixture was stirred vigorously for 1.5 hours. After dilution with water, the organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed successively with saturated aqueous sodium bicarbonate solution and brine, then dried (MgSO ₄ ) and evaporated. Purification by flash chromatography (silica gel, ethyl acetate-petroleum ether) gave the product as a light brown oil in a yield of 10.6 g (58% of theory).

b) Silver (3S, 4R) -3-bromo-1- (p-methoxybenzyloxycarbonylmethyl) -2-oxoazetidine-4-thiolate

A solution of p-methoxybenzyl [(3 S, 4 R) -4-acetylthio-3-bromo-2-oxoazetidin-1-yl] acetate (4.13 g, 0.01 mol) in methanol (90 mL) was stirred with stirring and under low light, was added to a solution of silver nitrate (2.27 g, 0.0133 mol) in methanol (90 mL). Then triethylamine (1.87 mL, 0.0133 mol) was added under ice-cooling. Stirring was continued for 1 hour at 5-10 ° C and then for half an hour at room temperature. The mixture was recooled (ice bath) and the precipitate was filtered off, washed twice with ice-cold methanol then hexane to give the title compound in 4.6 g yield (96%).

c) p-Methoxybenzyl [(35,47 R) -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] acetate

A solution of (35.47 R) -3-bromo-1- (p-methoxybenzyloxycarbonylmethyl) -2-oxoazetidine-4-thiolate (4.6 g, 0.0099 mol) in acetonitrile (100 mL) was reacted with benzyl bromide (1.76 mL, 0.015 mol) under nitrogen and the mixture was stirred under dim light for 48 hours. The solvent was evaporated, the residue leached with dichloromethane and the precipitated salts were filtered off. The filtrate was evaporated, the residue was purified by flash chromatography (silica gel, ethyl acetate-petroleum ether) to give the title compound as an oil in 3.37 g (76%). ^X H-NMR δ (CDC1 _3): 3.39, 4.02 (each 1H, d, J = 18.1 Hz, _NCH2), 3.76 (2H, s, _SCH2), 3.81 (3H, s, OCH ₃ ), 4.61, 4.91 (each 1H, d, J = 1.6 Hz, H ₃ + H ₄ ), 5.08 (2H, m, OCH ₂ ), 6, 89 (2H, m, 3,5- (4-Chloro-Jophi) -H), 7.22 to 7.339 (7H, m, Ph-H, 2,6- _(4-CH3 OPh) -H).

Example 79 (35,47 R) -N- (6-Phenylhexyl) -1- (4-benzylthio-3-bromo-2-oxoazetidin-1-yl) acetamide

a) R-Methoxybenzyl 2 - [(35,42 R) -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] -3-methylbut-2-enoate

P-Methoxybenzyl 2 - [(35,47 R) -4-mercapto-3-bromo-2-oxoazetidin-1-yl] -3-methylbut-2-enoate silver salt solution

(10 g, 20 mmol) in dry acetonitrile (100 mL) was treated with benzyl bromide (4 g, 24 mmol) and the resulting reaction mixture was heated at reflux temperature for 30 minutes. The reaction mixture was cooled to room temperature, filtered, evaporated to dryness and the residue purified by flash chromatography using pentane: hexane = 1: 1 as eluent. Evaporation of the appropriate fractions gave the product as a white solid (5.8 g, 59%), mp 70-72 ° C.

^X H-NMR δ (CDC1 _3): 1.93 (3H, s, _CH3), 2.23 (3H, s, CH _3),

3.66 (1H, dd, J = 2.9, 17.5 Hz, _SCH2), 3.79 (3H, s, _OCH3);

4.52 (1H, d, J = 1.8Hz, H ₃ ), 4.95 (1H, d, J = 1.9Hz, H ₄ ), 5.08 (2H, q, J = 12, 0 Hz, CO ₂ CH ₂ ), 6.84 to 6.90 (2H, m, 2,6-Ph-H), 7.13 to 7.31 (7H, m, 3.5Ph-H, Ph- H).

b) (35,47 R) -4-benzylthio-3-bromazetidin-2-one

A solution of p-methoxybenzyl 2 - [(3 S, 4 R) -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] -3-methylbut-2-enoate (2 g, 4 mmol) in dichloromethane (40 mL) ozone air was bubbled at -78 ° C. The progress of the reaction was monitored by IR spectrometry. Once disappeared peak 1 780 cm ^- * · ·, methanol (4 mL) along with a trace of sodium methoxide and dimethyl sulfide (1 ml) at room temperature, stirring was continued for 16 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography eluting with ether: pentane (1: 1). Evaporation of the appropriate fractions gave the product as a colorless oil (0.7 g, 64%).

¹ H NMR δ (CDCl ₃ ): 3.87 (2H, s, SCH ₂ ), 4.52 (1H, m, H ₄ ),

4.69 (1H, d, H ₃ ), 5.85 (1H, broad s, NH), 7.18-7.39 (5H, m, Ph-H).

c) N- (6-Phenylhexyl) [35,47R] -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] acetamide

A solution of (35.47 R) -4-benzylthio-3-bromazetidin-2-one (0.7 g, 2.6 mmol) in dry THF (25 mL) was treated with N- (6-phenylhexyl) bromoacetamide ( 0.8 g, 2.6 mmol), triturated potassium hydroxide (0.2 g, 3 mmol) and tetrabutyl monium hydroxide (0.1 g, 0.3 mmol). The mixture was stirred at room temperature for 4 hours and partitioned between ether and brine. The organic layer was separated, dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography using a 3: 1 mixture of ether and pentane as eluent. Evaporation of the appropriate fractions gave the title compound as an oil (0.63 g, 53%).

¹ H NMR δ (CDCl ₃ ): 1.21-1.66 (8H, m, (CH ₂ ) ₄ ), 2.59 (2H, t,

J = 7.4 Hz, CH ₂ ), 3.48, 3.82 (ki ach 1 H, d, J = 16 Hz, nch ₂ ; 1, 3.21 (2H, h, J = 6) , 00 Hz, ch ₂ ). , 3.37 (1H, dd, J = 5.15 Hz, H _3b ) 3.83 (2H, s, sch ₂ ), 4.59 (1 H, d, J = 1.6 Hz, H ₄ ), 4.89 (1H , d, J = 1.6 Hz, ₃ H); 6.04 (1H, broad t, NH), 7.14 to 7.36 (10H, m., Ph-H)

In Examples 80 and 81, starting from (35,47 R) -N- (6-phenylhexyl) -4-benzylthio-3-bromo-2-oxoazetidin-1-ylacetamide, the procedures described in Examples 2 and 3 were followed.

Example 80 (35.47?, ST?) -N- (6-Phenylhexyl) -4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl] acetamide

White crystals, m.p. 115 DEG-117 DEG C., yield 17.5% of theory.

Determined: C 57.9%, H 6.0%, N 6.0%,

624 ^ 29 ^ 263 $ requires: 57.0% C, 5.8% H, 5.5% N.

Example 81 (35,47 R, S5) -N- (6-Phenylhexyl) -4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl] acetamide

Colorless solid, mp 105-107 ° C, 15% yield.

Determined composition: 57.5% C, 6.0% H, 5.5% N,

C24H29N2O3S requires: 57.0% C, 5.8% H, 5.5% N.

Example 82 (47 R, S 5/47 R, S R) -N-6- (Phenylhexyl) -4-benzylsulfinyl-3-bromo-2

oxoazetidin-1-yl acetamide

(3S, 4R, SS) -N- (6-Phenylhexyl) -4-benzylsulphinyl-

3-Bromo-2-oxoazetidin-1-ylacetamide by any of the procedures given below gives (4R, SS / 4R, SR) -N-6- (phenylhexyl) -

4-Benzylsulfinyl-3-bromo-2-oxoazetidin-1-ylacetamide as a mixture whose NMR spectra were identical to those of Examples 30 and 31.

a) To a suspension of activated zinc powder (51.7 mg, 0.79 mmol) in dichloromethane (1.2 mL and acetic acid (0.4 mL)) was added N-6- with stirring at 5-10 ° C. (phenylhexyl) [(4R) -4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl] acetamide (0.2 g, 0.4 mmol) After stirring for 1 hour, the mixture was diluted with dichloromethane and water, organic layer The residue was crystallized from ethyl acetate to give the product as a 6: 1 mixture of 4R, SS: 4R, SR diastereoisomers in a yield of 48 mg (28 mg). % of the theoretical yield) and a melting point of 120 to 100%

121 ° C. The filtrate was evaporated and the residue was dissolved in ether to give a second crop as a 3: 1 mixture of distereoisomers, yield 50 mg (30%), mp 108-111 ° C.

b) A suspension of N-6- (phenylhexyl) [(4R) -4-benzylsulfinyl-3-bromo-2-oxo-azetidin-1-yl] acetamide (0.3 g, 0.59 mmol) and 10% palladium on activated carbon (50 mg) in ethanol was mixed with

0.59 mmol) of sodium bicarbonate solution (50 mg, in a small amount of water) and hydrogenated under 50 psi for 1 hour, then the catalyst was filtered off and the filtrate was evaporated to an oily residue which was evaporated to an oil. The combined extracts were dried (MgSO ₄ ) and evaporated, the oily residue was crystallized from ether to give the product as a 4: 1, SS / 4R, SR diastereoisomer mixture in a 3: 1 ratio in a yield of 0. 17 g (68% of theory) having a melting point of 110-113 ° C.

Example 83 (3S, 4R) -N- (6-Phenylhexyl) -1- (4-benzylthio-3-bromo-2-oxoazetidin-1-yl) acetamide

(a) (3S, 4S) -4-Benzylthio-3-bromo-2-oxoazetidin-1-yl) acetic acid

To a solution of p-methoxybenzyl [(3 S, 4 R) -4-benzylthio-3-bromo-2-oxoazetidin-1-yl] acetate (3.03 g, 6.7 mmol) in methanol (50 mL) at -5 to - 10 ° C 1 M potassium hydroxide solution (7.4 ml) was added dropwise with stirring. After two hours, the methanol was evaporated and the residue was diluted with water, extracted twice with ether, and the aqueous layer was acidified to pH 3 (2M HCl solution) under ice-cooling. The precipitated oil precipitated almost crystallized, filtered, washed and dried to give the title compound in an amount of 0.9 g (41% of theory), m.p. 138-140 ° C.

b) (3S, 4R) -N- (6-Phenylhexyl) -1- (4-benzylthio-3-bromo-2-oxoazetidin-1-yl) acetamide

Treatment of the latter acetic acid with 6-phenylhexylamine as described in Example 29 gave the title compound having the same spectra as those described in Example 79.

Example 84 (47 R, N) -N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-yl) acetamide

See Examples 154-157.

Example 85

N- [6- (4-Fluorophenyl) hexyl] -4- (4-methoxybenzylthio) -2-oxoazetidin-1-ylation

a) N- [6- (4-Fluorophenyl) hexyl] -1-bromoacetamide

A cooled solution of 6- (4-fluorophenyl) hexylamine (2.0 g) and Hunig's base (1.33 g) in dichloromethane (25 mL) was treated with bromoacetyl bromide (2.07 g) in dichloromethane (10 mL). The reaction was performed at 0-5 ° C. After working up and chromatography, N- [6- (4-fluorophenyl) hexane was obtained

Ayl] -1-bromoacetamide as a colorless solid in an amount of 2.71 g having a melting point of 50-51 ° C.

b) N- [6- (4-Fluorophenyl) hexyl] -4- (4-methoxybenzylthio) -2-oxoazetidin-1-ylacetamide

4- (4-Methoxybenzylthio) -2-oxoazetidinone (2 g) was reacted with the latter bromoacetamide (4 g) in dry THF in the presence of potassium hydroxide (0.7 g) and tetra-n-butylammonium bromide (0.4 g). 65 g) to give N- [6- (4-fluorophenyl) hexyl] -4- (4-methoxybenzylthio) -2-oxoazetidin-1-ylacetamide as colorless crystals, m.p. 53-55 ° C after chromatography. .

^X H-NMR δ (CDC1 _3): 1.33 (4H, m), 1.58 (4H, m), 2.56 (2H, t)

3.48, 2.94 (1H, dd), 3.24 (2H, m), 3.37 (1H, dd), 3.61 (1H,

d), 3.75 (1H, d), 3.77 (2H, s), 3.79 (3H, s), 4.79 (1H, dd), 6.09, 1H, m), 6, 82-7.26 (8H, m).

Example 86

N- (6- (2,4-Difluorophenyl) hexyl) -4- (4-benzylthio-2-oxoazetidin-1-yl) acetamide

By sequential treatment of (4-benzylthio-2-oxoazetidin-1-yl) acetic acid with 1-cyclohexyl-3- (2-morpholinetyl) carbodiimide meto-p-toluenesulfonate and 6- (2,4-difluorophenyl) hexylamine in dimethylformamide as described above Example 29 gave the title compound as a colorless solid, mp 65-66 ° C in 73% yield.

¹ H NMR δ (CDCl ₃ ): 1.30 to 1.36 (4H, m, 4xCH ₂ ), 1.50 to 1.60 (4H, m, 4xCH ₂ ), 2.58 (2H, t, J = 6.7 Hz, PhCH ₂ ), 2.93, 2.97

(1 H, dd, J = 2.4 15.6 Hz, ₃ H); 3.23 (2H, m, NHCH ₂ ), 3.35, 3.39 (1 H, dd, J = 5, 2, 15.2, h ₃ ). 3.57 3 71 (each 1H, d, J = 16.4 Hz, NCH ₂ ) 3.81 (2H, s, statues ₂ ), 4.80 (1H, m, h ₄ ), 6.02 (1 H, m _; , NH), 6.76 to 7.33 (8H, m, 2 Ph-H) ^{; T} c = 0

774 cm ^-1 .

Specified composition: 64.5 % c. 6.3 % H, 6.5 % N, ^ 24 ^ 28 ^ 2 ^ 2θ2 ^ requires: : 54,6 % c. 6.3 % H, 6.3 % N.

The following amides in Examples 87-96 were prepared by any of the methods described in Examples 29, 85 or 86.

Example 87

N- [6- (4-Chloro-phenyl) hexyl] -4- (4-methoxybenzylthio-2-oxo-azetidin-1-yl) acetamide

White crystals, m.p. 65-66 ° C, yield 89% of theory.

Determined Composition: 63.1% C, 6.5% H, 6.1% N, ^C 25 ^H 31 ^ClN 2 ° 3 ^S requires: 63.2% C, 6.6% H, 5.9% N.

Example 88

N- (6- (3,4-Difluorophenyl) hexyl) -4- (4-benzylthio-2-oxoazetidin1-yl) acetamide

Colorless solid, mp 53-54 ° C, yield 77% of theory.

NMR δ (CDCl ₃ ): 1.30 to 1.39 (4H, m, 4xCH ₂ ), 1.44 to 1.60 (4H, m, 4xCH ₂ ), 2.55 (2H, t, J = 7) 6 Hz, PhCH ₂ ), 2.91, 2.97 (1H, dd, J = 2.4, 15.4 Hz, H ₃ ), 3.23 (2H, m, NHCH ₂ ), 3.34 3.40 (1H, dd, J = 5.2, 15.4 Hz, H ₃ ), 3.56, 3.71 (each 1H, d, J = 16.8 Hz, NCH ₂ ), 3, 81 (2H, s, SOCH ₂ ), 4.80 (1H, m,

H ₄ ), 6.09 (1H, m, NH), 6.82-7.33 (8H, m, 2 Ph-H); τ = 1776 cm · · · ·.

Determined composition: 64.2% C, 6.3% H, 6.2% N, ^C 24 ^H 28 ^FN 2 ° 2 ^S requires: 64.6% C, 6.3% H, 6.3% N.

Example 89

N- (7-Phenylhept-1-yl) -4-benzylthio-2-oxoazetidin-1-yl acetamide

White crystalline solid, m.p. 63-65 ° C, yield 96% of theory.

^X NMR δ (cdci ₃ ) : 1.25 to 1.63 (10H, m), 2.59 (2 H, t) , 2.93 (1 H, dd), . 3.22 (2H, dt) 3.36 (1 H, dd), 3.50 ,. 3.71 (every 1H, d) 3.81 (2H, s), 3.81 (1 H, dd), 6.05 (1 H, broad s), 7.13 to 7.36 (10H, m).

Example 90

N- (6- [4-Chloro-phenyl] -hex-1-yl) - (4-methoxycarbonyl-benzylthio) -2-oxoazetidin-1-yl acetamide

White crystalline solid, m.p. 87-88 ° C, yield 88% of theory.

Assay Composition: 62.0% C, 6.2% H, 6.0% N, C 26 H 31 ClN 2 O 4 S requires: 62.1% C, 6.2% H, 6.0% N.

Example 91

N- (5-Phenylpentyl) -4-benzylthio-2-oxo-azetidinyl-1-yl-acetamide Colorless oil, yield 70% of theory.

¹ H NMR δ (CDCl ₃ ): 1.38-1.65 (6H, m, (CH ₂ ) ₃ ), 2.6 (2H, t,

J = 7.75 Hz), 2.89 to 2.96 (1H,

3:32 (2H, q, J = 6.68 Hz, NHCH _2),

H _3b ), 3.59, 3.70 (each 1H, d, (2H, s, SCH ₂ ), 4.80 (1H, m, H ₄ ),

7.33 (10 H, m, Ph-H).

dd, J = 2.5, 15 Hz, _H3a )

3.34 (1H, dd, J = 5.15Hz,

J = 17.00 Hz, _NCH2), 3.8

6.07 (1H, bs, NH);

Example 92

N- (6- (4-Bromo-phenyl) hexyl) -4-benzylthio-2-oxo-azetidin-l-yl-acetamide

Colorless solid, m.p. 73-75 ° C. Yield: 91%.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4x (¾), 2.54 (2H, t,

J = 8 Hz, _CH2 Ar), 2.94 (1H, dd, J = 2.15 Hz, ₃ H), 3.23 (2H, m, _NCH2), 3.37 (1H, dd, J = 5.15 Hz, H ₃ ), 3.56, 3.71 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.81 (2H, s, SCH ₂ ), 4.80 (1H, m, H ₄ ), 6.06 (1H, broad s, NH), 7.0-7.4 (9H, m, Ph-H +

BrPh-H).

Example 93

N- (6- (4-Fluorophenyl) hexyl) -4-benzylthio-2-oxoazetidin-1-yl acetamide

Colorless oil, yield 97% of theory.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4 x CH ₂ ), 2.56 (2H, 3 t, J = 8 Hz, CH ₂ Ar), 2.94 ( 1H, dd, J = 2.15 Hz, ₃ H), 3.23 (2Η, m, _NCH2), 3.37 (1H, dd, J = 5.15 Hz, ₃ H), 3.56, 3.72 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.81 (2H, s, SCH ₂ ), 4.81 (1H, m, H ₄ ), 6.07 (1H, broad s (NH), 6.9-7.4 (9H, m, Ph-H + FPh-H).

Example 94

N- [5- (4-Chlorophenyl) pentyl] -4-benzylthio-2-oxo-azetidin-1-yl acetamide

Colorless oil, yield 63.4% of theory.

^X H-NMR δ (CDC1 _3): 1.36 to 1.62 (6H, m, 3xCH _2), 2.56 (2H, t, J = 7.58 Hz, _Ar-2), 2.94 (1H, dd, J = 2.44 Hz, 15.38 Hz, H _3a ), 3.23 (2H, m, NHCH ₂ ), 3.36 (1H, dd, J = 5.17 Hz,

15.38 Hz, H _3b ), 3.62 & 3.55 (1H each, J = 16.8 Hz, NCH ₂ ), 3.80 (2H,, SCH ₂ Ph), 4.78 (1H, dd J = 2.46 Hz, 5.16 Hz, H ₄ ), 6.05 (1H, m, NHC = O), 7.06-7.33 (9H, m, 9xArH).

Example 95

N- [6- (2-Chlorophenyl) hexyl] -4-benzylthio-2-oxo-azetidin-1-yl acetamide

Colorless oil, yield 84% of theory.

^X H-NMR δ (CDC1 _3): 1.34 to 1.67 (8H, m, 4xCH _2), 2.71 (2H, t, J = 7.7 Hz, _Ar-2), 2.94 (1 H , dd, J = 2.5Hz, 15.4Hz,

H _3a ), 3.21 (2H, m, NHCH ₂ ), 3.37 (1H, dd, J = 5.2 Hz, 15.4

Hz, H _3b ), 3.55, 3.72 (1H each, J = 16.75 Hz, NCH ₂ ), 3.81 (2H, s, SCH ₂ Ph), 4.82 (1H, dd, J = 2.5 Hz, 5.2 Hz, H

6.09 (1H, m, NHOO), 7.10-7.33 (9H, m, 9xArH).

Example 96

N- (6- [4-Chlorophenyl] hex-1-yl) - (4-allyloxycarbonylbenzylthio) -2-oxoazetidin-1-yl acetamide

Light orange oil, 36% yield.

^X H-NMR δ (CDC1 _3): 1.25 to 1.59 (10H, m), 2.55 (2H, m), 2.94 (1H, dd), 3.38 (1H, dd), 3 53 and 3.83 (1H each, d), 3.96 (2H, s), 4.83 (2H, m), 5.27-5.45 (2H, m), 5.92-6, 09 (2H, m) 7.07 (1H, d), 7.22 (1H, d), 7.39 (1H, d), 8.02 (1H, d).

Example 97

N- [6- (4-Methylphenyl) -hexyl] - [4benzylsulphinyl-2-oxoazetidin1-yl] -acetamide

Colorless solid, m.p. 63 DEG-63 DEG C., yield 79% of theory.

¹ H NMR δ (CDCl ₃ ): 1.30 to 1.60 (8H, m, 4xCH ₂ ), 2.31 (3H, s, ArCH ₃ ), 2.55 (2H, t, J = 7.61) Hz, ArH ₂ ), 2.94 (1H, dd, J = 2.5, 15.4 Hz, H _3a ), 3.23 (2H, m, J = 13.75 Hz, NHCH),

3.38 (1H, dd, J = 5.17, 15.37 Hz, H _3b ), 3.63 (2H, dd, J =

16.75 Hz, COCH ₂ N), 3.81 (2H, s, ArCH ₂ S), 4.80 (1H, m, J = 5.14, 2.47 Hz, H ₄ ), 6.00 ( 1H, m, NH), 7.03-7.36 (9H, m, 9 * ArH).

The compounds of Examples 98 and 99 were prepared by the general procedure of Example 86, substituting the amine with phenylhexanols.

Example 98

6-Phenylhexyl- (4-benzylthio-2-oxo-azetidin-1-yl) acetate

Colorless oil, yield 33%.

¹ H NMR δ (CDCl ₃ ): 1.35-1.60 (8H, m, 4xCH ₂ ), 2.61 (2H, t, J = 7.64 Hz, ArCH ₂ ), 3.01 (1H, dd, 2.12 Hz, 5.37 Hz, _H3a ),

3.39 (1H, dd, J = 5.1Hz, 15.26Hz, H _3b ), 3.25, 4.00 (1H each, J = 18.09Hz, NCH ₂ ), 3.77 (2H, s , SCH ₂ Ph), 4.05 (2H, m, OCH ₂ ), 4.93 (1H, dd, J = 2.37 Hz, 5.07 Hz, H), 7.15-7

7.31 (10H, m, 10xArH).

Example 99

6- (4-Chlorophenyl) hexyl- [4-benzylthio-2-oxo-azetidin-1-yl] acetate

Colorless oil, 27% yield.

^{Χ Η} NMR δ (CDC1 _3): 1.31 1.68 (8H, m, 4xCH _2), 2.57 (2H, t, J = 7.61 Hz, _Ar-2), 2.97 (1 H, dd, 2.17 Hz, 15.17 Hz, _H3a ),

3.40 (1H, dd, J = 5.1 Hz, 15.25 Hz, H _3b ), 3.25, 4.00 (1H each, J = 18.10 Hz, NCH 2), 3.77 (2H, s 4.10 (2H, m, OCH 2), 4.93 (1H, dd, J = 2.37 Hz, 5.10 Hz, H ₄ ), 7.10 to

7.35 (9H, m, 9 * ArH).

Example 100

1- (9-Phenylnonyl) 4-benzylthio-2-oxoazetidin

Treatment of 4-benzylthio-2-oxoazetidine (1.35 g) with NaH (0.18 g) followed by 9-phenylnonyltriflate (2.8 g) afforded the title compound as a colorless oil (1.9 g). g, yield 68% of the theoretical yield).

³ H NMR δ (CDCl₃) 1.2 to 1.7 (14H, m, 7 x _CH2), 2.60 (2H, t, J = 8 Hz, _CH2 Ar), 2.8, 3, 2 (each 2H, m, H ₃ + NCH ₂ ) »3.76 (2H, s, SCH ₂ ), 4.59 (1H, m, H ₄ ), 7.15-7.35 (10H, m, Ph-H).

The following sulfoxides (Examples 101-130) were prepared by reacting the respective sulfides with mCPBA as described in Examples 2 and 3. When the substance is referred to as diastereomer 1, the compound is predominantly 4R, SR / 4S, SS. If it is described as diastereoisomer 2, it is predominantly 4R, SS / 4S, SR.

Example 101

N- [6- (4-Fluorophenyl) hexyl] -4- (4-methoxybenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1)

Colorless crystals, m.p.

149 ° C, 19% yield.

Designed for: C 63.2%, H 6.5%, N 6.0%, C 25 H 31 N 2 O 4: requires: C 63.3%, H 6.6%, N 5.9%.

Example 102

N- [6- (4-Fluorophenyl) hexyl] -4- (4-methoxybenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (Diastereoisomer 2)

Colorless crystals, m.p. 97 DEG-99 DEG C., 48% yield.

Determined composition: 63.1% C, 6.4% H, 5.8% N,

C25H31FN2O4S requires: 63.3% C, 6.6% H, 5.9% N.

Example 103

N- (6- (2,4-Difluorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1)

Colorless solid, mp 153 ° C, 19% yield.

^X H-NMR δ (CDC1 _3): 1.3 to 1.36 (4H, m, 4xCH _2), 1.50 to

2.57 (2H, t, J = 7.6Hz, PhCH ₂ ), 2.94, 2.98 (1H, dd, J =

4.8, 14.8 Hz, H ₃ ), 3.23 (2H, m, NHCH ₂ ), 3.44, 3.48 (1H, dd, J = 2.0, 14.8 Hz, H ₃ 3.70, 4.12 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 3.89, 4.05 (each 1H, d, J = 13.2 Hz, SOCH ₂ ), 4.51 (1H, m, H ₄ ), 6.64 (1H, m, NH), 6.72-7.41 (8H, m, 2 Ph-H); i.e. 1791 cm @ -1.

Determined composition: 62.3% C, 6.1% H, 6.1% N, ^C 24 ^H 28 ^F 2 ^N 2 ° 3 ^S requires: 62.3% C, 6.1% H, 6.1% N.

Example 104

N- (6- (2,4-Difluorophenyl) hexyl) - (4benzylsulphinyl-2-oxo-azetidin-l-yl) acetamide

Colorless solid, m.p. 114 DEG-116 DEG C. Yield: 46%.

¹ H NMR δ (CDCl ₃ ): 1.3 to 1.36 (4H, m, 4xCH ₂ ), 1.50 to 1.60 (4H, m, 4xCH ₂ ), 2.58 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.87, 2.90 (1H, dd, J = 2.4, 15.2 Hz, H ₃ ), 3.16, 3.19 (1H, dd, J =

5.6, 15.2 Hz, H ₃ ), 3.27 (2H, m, NHCH ₂ ), 3.88, 4.25 (each

1 H, d, J = 17.2 Hz, _NCH2), 3.99, 4.20 (each 1H, d, J =

13.2 Hz, SOCH ₂ ), 4.60 (1H, m, H ₄ ), 6.72-7.41 (9H, m,

(Ph-H, NH); tc _{= Q} 1793 cm ^{@ -1} .

Determined composition: - 62.3% C, 6.1% H, 6.2% N, ^C 24 ^H 28 ^F 2 ^N 2 ° 3 ^S requires: 62.3% C, 6.1% H, 6.1 % N.

Example 105

N- [6- (4-Chlorophenyl) hexyl] -4- (4-methoxybenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1)

Colorless crystals, m.p.

149 ° C, 32% yield.

Determined: 61.0% C, 6.2% H, 6.0% N,

C25H31ClN2O4S requires: 61.2% C, 6.4% H, 5.7% N.

Example 106

N- [6- (4-Chlorophenyl) hexyl] -4- (4-methoxybenzylsulfinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2)

Colorless crystals, m.p.

103 ° C, 31% yield.

Determined: 60.6% C, 6.2% H, 5.8% N,

C25H31ClN2O4S.0.3H2O requires: 60.5% C, 6.4% H, 5.6% N.

Example 107

N- (6- (3,4-Difluorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1)

Colorless solid, mp 171 ° C, 20% yield.

¹ H NMR δ (CDCl ₃ ): 1.3 to 1.36 (4H, m, 4xCH ₂ ), 1.50 to 1.60 (4H, m, 4xCH ₂ ), 2.54 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.93, 2.99 (1H, dd, J = 4.7, 14.9 Hz, H ₃ ), 3.22 (2H, m, NHCH ₂ ), 3 , 43,

3.48 (1H, dd, J = 2.2, 14.9 Hz, Hg), 3.70, 4.12 (each 1H, d, J = 17.4 Hz, NCH ₂ ), 3.89, 4.05 (each 1H, d, J = 13.1 Hz, S0CH _2), 4.51 (1H, m, H _4), 6.72 (1H, m, NH), 6.87 to 7.41 (8H, m, 2 Ph-H); tc _{= Q} 1791 cm ^-1 .

Determined Composition: C 62.3%, H 6.1%, N 6.2%, ^C 24 ^H 28 ^F 2 ^N 2 ° 3 ^S requires: C 62.3%, H 6.1%, 6.1% N.

Example 108

N- (6- {3,4-Difluorophenyl} hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Colorless solid, m.p. 115 DEG-116 DEG C., yield 58% of theory.

¹ H NMR δ (CDCl ₃ ): 1.3 to 1.36 (4H, m, 2xCH ₂ ), 1.50 to 1.60 (4H, m, 2xCH ₂ ), 2.54 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.87, 2.92 (11H, dd, J = 2.5, 15.3 Hz, H ₃ ), 3.16, 3.19 (1H, dd, J = 5.4, 15.3 Hz, H ₃ ), 3.27 (2H, m, NHCH ₂ ), 3.88, 4.25 (each

1H, d, J = 17.2 Hz, NCH ₂ ), 3.98, 4.21 (each 1 H, d, J =

13.0 Hz, SOCH ₂ ), 4.60 (1H, m, H ₄ ), 6.85 to 7.41 (9H, 45 m,

7PH-H, NH); tc _{= Q} 1793 cm ^{@ -1} .

Determined composition: 62.4% C, 6.1% H, 6.1% N, ^C 24 ^H 28 ^F 2 ^N 2 ° 3 ^S requires: 62.3% C, 6.1% H, 6.1% N.

Example 109

N- (7-Phenylhept-1-yl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 1)

Colorless crystalline solid, m.p.

143 DEG-144 DEG C., yield 27% of theory.

Determined composition: 67.7% C, 7.1% H, 6.3% N, ^ 25 ^ 32 ^ 2θ3 ^ 'θ' ^ 1 ^ 2θ requires: 67.9% C, 7.3% H, 6% , 3% N.

Example 110

N- (7-Phenylhept-1-yl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 2)

Colorless crystalline material, melting point 133-133 ° C, yield 40% of theory.

Determined: C 67.8%, H 7.1%, N 6.3%,

C25H32N2O3S requires C 68.2% H 7.3% N 6.4%

Example 111

N- (6- [4-Chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1)

It forms white crystals, m.p. 188 DEG-189 DEG C., yield 17% of theory.

, The composition: 60.1% C, 6.0% H, 5.5% N, ^C 26 ^H 31 ^C1N 5 ^S 2 ° ^{wherein the back} I ^t: 60.2% C, 6.0% H, 5. 4% N.

Example 112

N- (6- [4-Chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2)

It forms white crystals, m.p.

141 ° C, 51% yield.

Determined Composition: C 60.1%, H 6.0%, N 5.4%, ^C 26 ^H 31 ^ClN 2 ° 5 ^S requires: C 60.2%, H 6.0%, N 5.4%.

Example 113

N- (6-phenylhex-l-yl) - (4-ethoxycarbonylbenzyl-sulfinyl) -2-oxoazetidin-l-yl-acetamide

Colorless crystals, m.p.

178 ’C, 51% yield.

Determined composition: 64.3% C, 6.7% H, 5.7% N,

C27H34N2O5S.0,3H ₂ 0 requires: 64.3% C, 6.9% H, 5.6% N.

Example 114

N- (6- (4-Chlorophenyl) hex-1-yl) - (4-allyloxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2)

White crystalline material, m.p. 110 DEG-112 DEG C., 30% yield.

Determined: C 61.7%, H 6.1%, N 5.1%,

C28H33ClN2O5S requires: 61.7% C, 6.1% H, 5.1% N.

Example 115

N- (5-Phenylpentyl) -4-benzylsulphinyl-2-oxo-azetidinyl-1-yl acetamide

Colorless solid, m.p.

142 DEG C., yield 6.5% of theory.

^T C = 0 1,790, 1,690 cm -1 · · · ·.

Determined composition: 66.6% C, 6.7% H, 6.8% N, 23.28, 28.22, 3.28 requires: 67.0% C, 6.8% H, 6.8% N.

Example 116

N- (5- (4-Chlorophenyl) pentyl) -4-benzylsulphinyl-2-oxo-azetidin-1-yl acetamide (Diastereoisomer 1)

It forms white crystals, m.p.

147 C, 31.5% yield.

Determined composition: 61.94% C, 6.1% H, 6.8% N, 23.27%, requires: 61.8% C, 6.1% H, 6%, 3% N.

Example 117

N- (5- (4-Chlorophenyl) pentyl) -4-benzylsulfinyl-2-oxo-azetidin-1-ylacetamide (Diastereoisomer 2)

Colorless crystals, m.p.

119 ´C, yield 53.8% of the theoretical yield.

Determined Composition: 61.7% C, 5.9% H, 6.4% N, ^C 23 ^H 27 ^ClN 2 ° 3 ^S requires: 61.8% C, 6.1% H, 6.3% N.

Example 118

N- [5- (2-Chloro-phenyl) -hexyl] -4-benzylsulfinyl-2-oxo-azetidin-1-yl acetamide (diastereoisomer 1)

Colorless crystals, m.p. 96-98 ° C, yield 35.2. % of the theoretical yield.

Found: C 61.82, H 6.18, N 6.14,

C24H29CIN2O3S.0,3H ₂ O requires:

H, 6.40; N, 6.01.

Example 119

N- [5- (2-Chloro-phenyl) -hexyl] -4-benzylsulfinyl-2-oxo-azetidin-1-ylacetamide

Colorless crystals, m.p. 86 DEG-88 DEG C., yield 57% of theory.

Determined: 62.6% C, 6.2% H, 6.1% N,

C24H29ClN2O3S requires: C 62.5%, H 6.3%, N 6.1%.

Example 120

N- (6- (4-Bromophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 1)

Colorless solid, m.p.

179 ° C, 30% yield.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4 x CH ₂ ), 2.53 (2H, t, J = 8 Hz, CH ₂ Ar), 2.95 (1H δ d, J = 5.15 Hz, H ₃ ), 3.21 (2H, m, NCH 2), 3.44 (1H, dd, J = 2.15 Hz, H ₃ ), 3.72, 4, 10 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.89, 4.04 (each 1H, d, J = 13 Hz, SOCH ₂ ), 4.54 (1H, m, H ₄ ), 6.74 (1H, broad s, NH), 7.0 to 7.0

7.4 (9H, m, Ph - H + BrPh - H); t _{c = 0} 1792 cm ¹

Determined Composition: C 56.9%, H 5.7%, N 5.6%, ^C 24 ^H 29 ^BrN 2 ° 3 ^S requires: C 57.0%, H 5.8%, N 5.5%.

Example 121

N- (6- (4-Bromophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 2)

Colorless solid, m.p.

113 DEG C., yield 45% of theory.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4 x CH ₂ ), 2.54 (2H, t, J = 8 Hz, CH ₂ Ar), 2.88 (1H δ d, J = 2.15 Hz, H ₃ ), 3.18 (1H, dd, J = 5.15 Hz, H ₃ ), 3.25 (2H, m, NCH ₂ ), 3.89, 4 , 24 (each

1 H, d, J = 17 Hz, _NCH2), 3.98, 4.19 (each 1H, d, J = 13 Hz, _SOCH2), 4.62 (1 H, m, H _4), 7.0 up to 7.4 (10H, m, Ph - H + BrPh - H + NH); x _{c = 0} 1793 cm ¹ .

, The composition: 57.0% C, 5.7% H, 5.6% N, ^ 24 ^ 29® ^Γ ^ ^ 2θ3 requires 57.0% C, 5.8% H, 5.5% N.

Example 122

N- (6- (4-Fluorophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 1)

Colorless solid, m.p. 163 DEG-164 DEG C. Yield: 33%.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4 x CH ₂ ), 2.55 (2H, t, J = 8 Hz, CH ₂ Ar), 2.96 (1H δ d, J = 5, 15 Hz, H ₃ ), 3.22 (2H, m, NCH ₂ ), 3.46 (1H, dd, J = 2.15 Hz, H ₃ ), 3.71, 4 12 (each 1H, d, J = 17 Hz, NCH ₂ ), 3.89, 4.06 (each 1H, d,

J = 13 Hz, _SOCH2), 4.53 (1H, m, h ₄ ), 6.70 (1 H, wide with, NH), 6.9, 7.1 (4H, 2xm, FPH-H) , 7, 25 to 7.35 (5H, 2xm, Ph-H); x _{c = 0} 1,791 cm ^-1 . Specified composition: 64.8 % C, 6.5% H, 6, 2% N, C24H29FN2O3S requires: 64.8 % C, 6.6% H, 6, 3% N.

Example 123

N- (6- (4-Fluorophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 2)

Colorless solid, m.p.

119 'C, 35% yield.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (8H, m, 4 x CH ₂ ), 2.56 (2H, t,

J = 8 Hz, _CH2 Ar), 2.89 (1 H, d, (1 H, dd, J = 5, 15 Hz, ₃ H), 3.25 (each 1H, d, J = 17 Hz, _NCH2 )

J = 2.15 Hz, H ₃ ), 3.18 (2H, m, NCH ₂ ), 3.89, 4.24, 3.99, 4.19 (each 1H, d,

J = 13 Hz, S0CH _2), 4.60 (1 H, m, ₄ H), FPh-H), 7.2 to 7.5 (6H, m, Ph-H + NH);

Determined composition: 64.8% C,

6.93, 7.10 (4H, 2xm,

793 cm ¹ .

6.5% H, 6.2% N, ^ 24 ^ 29 ^ 2θ3 ^ requires:

64.8% C,

H, 6.6; N, 6.3.

Example 124

6-Phenylhexyl (4-benzylsulfinyl-2-oxo-azetidin-1-yl) acetate (2: 1 diasfereoisomer 2: diastereoisomer 1)

Colorless crystals, m.p. 64-67 ° C, yield 80% of theory.

Determined composition: 66.5% C, 6.8% H, 3.3% N,

C24H29NO4S. 0.8 CH2Cl2 requires:

64.8% C, 6.6% H, 6.3% N.

Example 125

6- (4-Chlorophenyl) hexyl- (4-benzylsulfinyl-2-oxo-azetidin-1-yl) acetate

Colorless oil material, yield 25 % theory yield. Specified composition: 61.3 % C, 6.1 % H, 3.1 % N, ^C 24 ^H 28 ^C1NO 4 ^S · ^{14 14 CH} 2 ^C1 2 require 1 e: 61.2 % C, 6.0 % H, 3.0 % N.

Example 126

1- (9-Phenylnonyl) -4-benzylsulfinyl-2-oxoazetidine (diastereoisomer 1)

Colorless solid, m.p. 87-88 ° C, 10% yield.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (14H, m, 7 x CH ₂ ), 2.59 (2H, t, J = 8 Hz, CH ₂ Ar), 2.85 (1H , dd, J = 5, 15 Hz, ₃ H), 3.25. (2H, m, NCH ₂ ), 3.40 (1H, dd, J = 2, 15 Hz, H ₃ ), 3.86, 4.01 (each 1H, d, J = 13 Hz, SOCH ₂ ), 4.33 (1H, m, H ₄ ), 7.15-7

7.45 (10 H, m, Ph-H); t _{c = 0} 1 777 cm- ¹ .

Example 127

1- (9-Phenylnonyl) -4-benzylsulfinyl-2-oxoazetidine (75% of diastereoisomer 2)

Colorless solid, mp 59-61 ° C, 34% yield.

¹ H NMR δ (CDCl ₃ ) :( Dia 2) 1.2-1.7 (14H, m, 7 x CH ₂ ), 2.46 (1H, dd, J = 2.15 Hz, H ₃ ), 2.59 (2H, t, J = 8 Hz, _CH2 Ar),

2.96 (1H, dd, J = 5, 15 Hz, ₃ H), 3.37 (2H, m, _NCH2), 3.98, 4.07 (each 1H, d, J = 13 Hz, SOC ₂ ), 4.37 (1H, m, H ₄ ),

7.15 to 7.40 (10H, m, Ph-H).

Example 128

N- [6- (4-Methylphenyl) -hexyl] - [4-benzylsulfinyl-2-oxo-azetidin-1-yl] acetamide

Colorless solid, m.p.

157 ° C, 29% yield.

Assay Composition: 67.9% C, 7.1% H, 6.3% N, 25%, 32%, 32% requires: 68.2%, 7.0%, 6.4% N.

Example 129

N- [6- (4-Methylphenyl) -hexyl] - [4-benzylsulphinyl-2-oxo-azetidin-1-yl] acetamide

Colorless solid, m.p. 94 ° C, yield 59% of theory.

Designed for: 68.0% C, 7.2% H, 6.3% N, 25% 32, 32% requires: 68.2% C, 7.3% H, 6.4% N.

Example 130

N- (6- (4-Chlorophenyl) hex-1-yl) - ((4-carboxybenzylsulphinyl) -2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

A solution of N- (6- (4-chlorophenyl) hex-1-yl) - ((4-allyloxycarbonylbenzylsulfinyl) -2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) was stirred for 16 hours at 25 ° C. (1.25 g), tetrakistriphenylphosphine palladium (0) (80 mg), triphenylphosphine (635 mg), and pyrrolidine (171 mg in dichloromethane (100 mL). The reaction mixture was then purified by chromatography (fine silica, dichloromethane - 50% acetone). in dichloromethane) and without concentration gave N- (6- (4-chlorophenyl) hex-1-yl) - ((4-carboxybenzylsulphinyl) -2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) as a white solid m.p. 195-197 ° C, 62% yield.

, The composition: 59.0% C, 5.7% H, 5.5% N, ^C 25 ^H 29 ^C1N 2 ° 3 ^S · ^{0-1 H} 2 ° requires 59.2% C, 5.8% H , 5.5% N.

The following sulfones (Examples 131-144) were prepared

By reacting the respective sulfides or sulfoxides with an excess of m-CPBA as described in Example 4.

Example 131

N- [6- (4-Fluorophenyl) hexyl] -4- (4-methoxybenzylsulfonyl) 2-oxo-azetidin-l-yl-acetamide

Colorless crystals, m.p. 115-118 ° C, yield 37% of theory.

Assay Composition: 61.0% C, 6.3% H, 5.7% N, ^C 25 ^H 31 ^FN 2 ° 5 ^S requires: 61.2% C, 6.4% H, 5.7% N.

Example 132

N- [6- (2,4-Difluorophenyl) hexyl] - (4-benzylsulfonyl-2-oxo-azetidin-l-yl) acetamide

Colorless solid, mp 130-131 ° C, yield 68% of theory.

^{Χ Η} NMR δ (CDC1 _3): 1.3 to 1.36 (4H, m, 4xCH _2), 1.50 -1.60 (4H, m, 4xCH _2), 2.58 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.97, 3.03 (1H, dd, J = 2.6 15.42 Hz, H ₃ ), 3.08, 3.14 (1H, dd, J =

5.0, 15.4 Hz, H ₃ ) 3.24 (2H, m, NHCH ₂ ), 3.84, 3.94 (each

1 H, d, J = 16.9 Hz, _NCH2), 4.31, 4.37 (each 1H, d, J =

14.3 Hz, SO ₂ CH ₂ ), 4.81 (1H, m, H ₄ ), 6.0 (1H, m, NH), 6.72-7.44 (9H, m, 2Ph-H) ; t _{c = Q} 1797 cm ^-1 .

Designed for: C 60.1%, H 5.9%, N 5.9%, 24% C, 24%, C 24%, requires: C 60.2%, H 5.9%, N 5.9%.

Example 133

N- [6- (4-Chlorophenyl) hexyl] -4- (4-benzylsulfonyl) -2-oxoazetidin-1-yl acetamide

Colorless crystals, m.p. 118-120 ° C, yield 94% of theory.

Assay Composition: 59.0% C, 6.1% H, 5.5% N, C 25 H 31 ClN 2 O 5 S requires: 59.2% C, 6.2% H, 5.5% N.

Example 134

N- [6- (3,4-Difluorophenyl) hexyl] - (4-benzylsulfony1-2-azetidin-1-yl) acetamide

Colorless solid, mp 114-115 ° C.

¹ H NMR δ (CDCl ₃ ): 1.3 to 1.36 (4H, m, 4xCH ₂ ), 1.50 to 1.60 (4H, m, 4xCH ₂ ), 2.55 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.97, 3.03 (1H, dd, J = 2.5 15.4 Hz, H ₃ ), 3.08, 3.14 (1H, dd, J = 5.0, 15; 4 Hz, H ₃ ) 3.24 (2H, m, NHCH ₂ ), 3.84, 3.94 (each 1H, d, J = 16.9 Hz, NCH ₂ ), 4 , 31, 4.37 (each 1H, d, J = 14.2 Hz, SO ₂ CH ₂ ), 4.83 (1H, m, H ₄ ), 6.04 (1H, m, NH), 6, 82-7.44 (9H, m, 2 Ph-H); 1,797 cm ^-1 .

, The composition: 60.1% C, 5.9% H, 5.9% N, ^ 24 ^ 28 ^ 2 ^Ρ 2θ4 ³ requires: 60.2% C, 5.9% H, 5.9% N.

Example 136

N- (7-Phenylhept-1-yl) -4-benzylsulphonyl) -2-oxoazetidin-1-yl acetamide

White crystalline solid, m.p. 114-115 ° C, 85% yield.

Determined composition: 65.9% C, 6.9% H, 6.1% N,

C25H32N2O4S.0,3 H ₂ 0 requires: 65.0% C, 7.1% H, 6.1% N.

Example 137

N- [6- (4-chlorophenyl) hexyl] - (4- (4-carboxybenzylsulphonyl) 2-oxo-azetidin-l-y1) acetamide

Colorless crystals, m.p. 173-174 ° C, yield 40% of theory.

Determined composition: 56.9% C, 5.7% H, 5.1% N, ^C 26 ^H 31 ^ClN 2 ^O 6 ^S - ° ^5H 2 ° requires: 56.8% C, 6.0% H, 5,1% N.

Example 138

N- [5- (4-Chloro-phenyl) -pentyl] -4-benzylsulfonyl) -2-oxoazetidin-1-yl) acetamide

Colorless crystals, m.p. 109-110 ° C, yield 81.7% of theory.

Determined Composition: C 59.6%, H 5.7%, N 6.0%, ^C 23 ^H 27 ^ClN 2 ° 4 ^S requires: C 59.7%, H 5.9%, 6.1% N.

Example 139

N- [5- (2-Chloro-phenyl) -hexyl] -4-benzylsulfonyl) -2-oxoazetidin-74 (1-yl) acetamide

Colorless crystals, m.p. 81-83 ° C, yield 84% of theory.

Determined: 60.5% C, 6.1% H, 5.9% N,

C24H29ClN2O4S requires: C 60.5%, H 6.1%, N 5.9%.

Example 140

N- (6- (4-fluorophenyl) hexyl] -4-benzylsulfonyl) -2-oxoazetidin1-yl) acetamide

Colorless solid, m.p. 132-133 ° C, yield 76% of theory.

¹ H NMR δ (CDCl ₃ ): 1.2-1.6 (8H, m, 4xCH ₂ ), 2.57 (2H, t,

J = 8 Hz, _CH2 Ar), 3.02 (1H, dd, J = 2,15, 15 Hz, ₃ H), 3.10 (1H, dd, J = 5.0, 15 Hz, ₃ H 3.25 (2H, m, NCH ₂ ), 3.85, 3.94 (each 1H, d, J = 17 Hz, NCH ₂ ), 4.34, (2H, s, SO ₂ CH ₂ ), 4.82 (1H, m, H ₄ ), 6.0 (1H, broad s, NH), 6.9-7.15 (5H, m, 2 Ph-H); t _{c = 0} 1797 cm ¹ .

Determined composition: C 62.5%, H 6.3%, N 6.2%, C 24 H 29 F 2 O 4 requires: C 62.6%, H 6.4%, N 6.1%.

Example 141

6-Phenylhexyl- (4-benzylsulfonyl-2-oxoazetidin-1-yl) acetate Colorless oil, yield 2.3% of theory.

¹ H NMR δ (CDCl ₃ ): 1.32-1.65 (8H, m, 4xCH ₂ ), 2.60 (2H, t, J = 7.64 Hz, CH ₂ Ar), 2.95 (1H , dd, 2.35 Hz, 15.35 Hz H _3a ),

3.11 (1H, dd, J = 5.12, 15.39 Hz, H _3b ), 3.72, 4.27 (each 1H, d, J = 18.3 Hz, NCH ₂ ), 4.34 (2H, s, SCH ₂ Ph), 4.11 (2H, m, OCH ₂ ), 4.91 (1H, dd, J = 2.36 Hz, 5.08 Hz, H ₄ ),

7.15 to 7.43 (10H, m, 10xArH).

Example 142

6- (4-Chlorophenyl) hexyl- (4-benzylsulfonyl) -2-oxo-azetidine-yl) acetate

Colorless crystals, m.p. 77 DEG-79 DEG C., yield 50% of theory.

Specified composition:

C 14 H 16 ClNO 5 S requires:

60.3% C, 5.9% H, 3.0% N,

% H, 5.9%; N. 2.9%.

Example 143

1- (9-Phenylnonyl) 4-benzylsulfonyl) -2-oxoazetidin

Colorless solid, mp 69-70 ° C, yield 59% of theory.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (14H, m, 7xCH ₂ ), 2.59 (2H, t, J = 8 Hz, CH ₂ Ph), 2.92 (1H, dd) 2.15 H ₃ ), 3.1 (2H, m, H ₃ + NCH ₂ ), 3.4 (1H, m, NCH ₂ ), 4.28 (2H, s, SCH ₂ ), 4.50 (1H, m, H ₄ ), 7.1-7.5 (10H, m, Ph-H); t _{c = 0} 1782 cm ^-1 .

, The composition: 70.0% C, 7.6% H, 3.4% N, ^C 25 ^H 33 ^NO 3 ^S Y ^{to the} Duje: 70.2% C, 7.8% H, 3.3% N .

Example 144

N- [6- (4-Methylphenyl) -hexyl] - [4-benzylsulfonyl] -2-oxoazetidin-1-yl] acetamide

Colorless solid, m.p. 125-126 ° C, yield 67% of theory.

Determined: C 65.3%, H 6.8%, N 6.0%,

C25H32N2O4S requires: 65.8% C, 7.1% H, 6.1% N.

Example 145

N- (6-phenylhexanoyl) - (4-benzylthio-2-oxo-azetidin-l-yl]) acetamide

a) (4-Benzylthio-2-oxoazetidin-1-yl)] - acetamide Book number 50516/061

A solution of (4-benzylthio-2-oxoazetidin-1-yl)] acetic acid (1.0 g, 3.98 mmol) in dry tetrahydrofuran (25 mL) was treated with 1,1-carbonyldiimidazole (0) under nitrogen. (71 g, 4.38 mmol) and then stirred at room temperature for 2 hours. Ammonia gas was then bubbled through the reaction mixture for 30 minutes. The reaction mixture was stirred for an additional 60 minutes, diluted with ethyl acetate (75 mL), washed with aqueous saturated NaHCO ₃ , brine, dried (MgSO ₄ ) and evaporated under reduced pressure. Purification by column chromatography using 20: 1 methylene chloride: MeOH gave the product as a colorless solid, m.p. 127-128 ° C (0.92 g, 92%).

Ί6 ¹ H NMR δ (CDCl ₃ ): 2.93, 2.99 (1Η, dd, J = 2.4, 15.4 Hz,

H ₃ ), 3.36, 3.42 (1H, dd, J = 6.2, 15.4 Hz, H ₃ ), 3.79 (each 1H, d, J = 17 Hz, NCH ₂ ), 3 , 82 (2H, s, _SCH2), 4.85 (1 H, m, H _4), 5.62 (1 H, br s, NH), 6.07 (1 H, br s, NH), 7.23 up to 7.38 (5H, m, Ph-H).

b) 6-Phenylhexanoyl chloride

Phenylhexanoic acid (2.5 g, 13 mmol) was mixed with thionyl chloride (3.0 mL, 41.1 mmol) and the mixture was stirred at reflux temperature for 3 hours. The mixture was evaporated under reduced pressure to remove thionyl chloride and then distilled at 92-95 ° C / 0.1 mbar to give the product as a colorless oil (2.57 g, 94%).

c) N- (6-Phenylhexanoyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide

A solution of (4-benzylthio-2-oxoazetidin-1-yl)] acetamide (0.63 g, 2.52 mmol) in dry THF (15 mL) was added to a sodium hydride suspension (60% suspension in oil, 0,10 g,

2.5 mmol) in dry THF at -10 ° C under a nitrogen atmosphere. The reaction mixture was stirred at -10 ° C for 10 min and then treated dropwise with a solution of 6-phenylhexanoyl chloride (0.58 g, 2.75 mmol) in dry THF (5 mL) over 2 min. The temperature was maintained at -10 ° C. Then take a cooling bath! The reaction mixture was treated with sodium hydride (50 mg, 1.25 mmol) and phenylhexanoyl chloride (0.29 g, 1.38 mmol) in dry THF (2 mL). The reaction mixture was stirred for 60 minutes, poured onto a mixture of ice and brine (100 mL), extracted with ethyl acetate (2 x 50 mL). The organics were combined, washed with aqueous saturated sodium bicarbonate, brine, dried (MgSO ₄ ) and evaporated under reduced pressure to give an orange-colored oily residue. Purification by repeated column chromatography using hexane: ethyl acetate (3: 1 to 1: 1) as eluent gave the product as a colorless oil (0.22 g, 21% yield) containing 10% 6-phenylhexanoic acid .

^T H NMR δ (CDC1 _3): 1.3 to 1, J = 7.4 Hz, NHCOCH _2), 2.62

2.96, 3.02 (1H, dd, J = 2.4, dd, J = 5.1, 15.3 Hz, H ₃ ),

18.8 Hz, NCH ₂ CO), 3.76 (2H, (6H, m, 3xCH ₂ )), 2.44 (2H, t, (2H, t, J = 7.6 Hz, PhCH ₂ ),

15.3 Hz, H ₃ ), 3.39, 3.45 (1H, 3.61, 4.32 (each 1H, d, J =, SCH ₂ ), 4.9 (1H, m, H ₄ ), 7.1-7.3 (10H, m, Ph-H), 8.17 (1H, m, NH).

Example 146

N- (9-phenylhexanoyl) - (4-benzylsulphinyl-2-oxoazetidin1-yl) acetamide

Reaction of N- (6-phenylhexanoyl) - (4-benzylthio-2-oxoazetidine)

1-yl] acetamide with mCPBA analogously to Example 2 gave the title compound as a 50:50 mixture of diastereoisomers. The product was a colorless solid, mp

153-156 ° C, product yield 37% of the theoretical yield.

^T H NMR δ (CDC1 _3): 1.36 (4H, m, 2 x CH _2), 1.64 (8H, m, 4xCH _2), 3.39 (4H, m, 2xPhCH _2), 2.48, 2 52 (1H, dd, J = 2.4, 15.2 Hz, H ₃ ), 2.60 (4H, m, 2xNCH ₂ ), 2.96, 2.99 (1H, dd, J = 4, 8

14.8 Hz, H ₃ ), 3.03, 3.07 (1H, dd, J = 5.2, 15.2 Hz, H ₃ ), 3.39, 3.43 (1H, J = 2, 0.14.8 Hz, H ₃ ), 3.9-4.6 (8H, m,

2xNCH ₂ , 2x SOCH ₂ ), 4.72 (1H,

7.16 to 7.40 (20H, m, 4xPh-H), NH); t _{c = Q} 1,782 cm ^-1 .

Specified composition:

^ 24 ^ 28 ^ 2θ4 ^ requires:

m, H ₄ ), 4.81 (1H, m, H ₄ ),

8.49 (1 H, s, NH), 9.01 (1 H,

65.3% C,

65.4% C,

6.4% H,

6.4% H,

6,4% N,

6,4% N.

Example 147

N- (5-Phenylpentyloxy) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide

Treatment of (4-benzylthio-2-oxo) azetidin-1-yl] acetic acid with N- (5-phenylpentyl) hydroxylamine as described in Example 1 and Example 86 afforded N- (5-phenylpentyloxy) (4-benzylthio-2- oxoazetidin-1-yl) acetamide as a colorless oil in 55% yield.

¹ H NMR δ (CDCl ₃ ): 1.31-1.43 (2H, m, CH ₂ ), 1.53-1.67 (4H, m, 2xCH ₂ ), 2.58 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.85, 2.91 (1H, dd, J = 2.4, 15.0 Hz, H ₃ ), 3.41 (1H, d, J = 18.2 Hz, from NCH ₂ ), 3.74 to 3.91 (5H, m, 1 of NCH ₂ , SCH ₂ , NHOCH ₂ ),

4.87 1H, m, H ₄ ), 7.10-7.35 (10H, m, 2xPh-H), 10.8 (1H, s, NH).

Reaction of N- (5-phenylpentyloxy) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide with m-CPBA as described in Example a 3 gave the following two compounds.

Example 148

N- (5-Phenylpentyloxy) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereomer 1)

Colorless solid, m.p.

179 ´C, yield 23% of the theoretical yield.

³ H NMR δ (DMSO 350K): 1.41 and 1.38 (2H, m, _CH2), 1.56

1.62 (4H, m, 2xCH ₂ ), 2.58 (2H, t, J = 7.6 Hz, PhCH ₂ ), 3.0 to 3.17 (2H, m, H ₃ ), 3.40 , 3.65 (each 1H, m, S0CH _2), 3.75

(2H, t, J = 6.5 Hz, NHOCH _2), 3.85. 4.10 (every 1H, d, J = 13 Hz, NCH ₂ ), 4.87 (1H, m, h ₄ ), 7.14 to 7.35 (10H, m 2xPh-H), 10.9 (1H, s, NH). Specified composition: 63.8 % C, 6.5% H, 6.5% N, ^<3 23 ^ίί 28 ^ 2θ4 ^ ³ > θ% H ₂ O) requires: 63.8 % C, 6.6% H, 6.5% N.

Example 149

N- (5-Phenylpentyloxy) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (Diastereoisomer 2)

Colorless oil, yield 39% of theory.

³ H NMR δ (DMSO 350K) 1.36 (2H, m, _CH2), 1.56 1.61 (4H, m, 2 x CH _2), 2.58 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.9, 3.2 (2H, m, H ₃ ), 3.75 (2H, t, J = 6.6 Hz, NHOCH ₂ ), 3.9, 4.05 (each 1H, m, SOCH ₂ ), 4.04, 4.20 (each 1H, d, J = 12.9 Hz, NCH ₂ ), 4.79 (1H, m, H ₄ ), 7.16-7, 37 (10H, m, 2xPh-H), 10.95 (1H, s, NH), tQ ₌ Q 1788 cm ^'1'

Determined composition: 63.7% C, 6.6% H, 6.2% N, ^C 23 ^H 28 ^N 2 ° 4 ^S < ^{+ 3} ' ⁴ % ^C 4 ^H 8 ° 2'% ^H ₂ 0) requires:

63.7% C, 6.7% H, 6.4% N.

Example 150

R-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide

Reaction of R - (-) - (4-benzylthio-2-oxoazetidin-1-yl) acetic acid [prepared from the corresponding racemic acid by recrystallization of the quinchonidine salt [α] D = - 43 ° (c =

1, CHCl ₃ )], with dicyclohexylcarbidiimide and 6- (4-chlorophenyl) hexylamine as described in Example 29, gave RN- (6- (4-chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) ) acetamide in the form of a colorless solid,

Product MONEY 71 "C NMR δ ^T (CDC1 _3): 1.33 (4 H, m, Hz, PhCH _2), 2.92, and 3.24 (2H, m,

Hz, H ₃ ), 3.54, (1H, s, SCH ₂ ), 7.33 (9H, m,

2.97 (1 H, dd, NHCH _2), 3.33,

3.72 (each 1H,

4.80 (1H, m, 2.times.Ph-H).

yield 83% of theory. 2xCH ₂ , 2.56 (2H, t, J = 2.4, 15.4 Hz, H ₃ ), 3.39 (1H, dd, J = 5.2, d, J = 16.8 Hz, NCH ₂ ),

₄ H), 6.11 (1H, m, tQ_Q 1776 Cm ^- · '·;

(c = 1.1% w / v CHCl ₃ ) at 25 ° C.

Determined composition: 64.8% C, 6.5% H,

₂ C 4 H ₂ 9C1N ₂ O ₂ S requires: 64.8% C, 6.6% H,

J = 7.6, 3.22

15.4

3.81

NH), 7.07 to [α] _D = + 36 °

Example 151

S-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide

Prepared acid 4S- (4-benzylthio-2-oxoazetidin1-yl) acetic acid, [a] _D = + 34 DEG (c = 1.1% CHC1 ₃₎ and recrystallization of the salt of racemic formed with cinchonine or brucine. This chiral pure acid was reacted with 4- (chlorophenyl) hexylamine as described in Example 29 to give the title compound as a colorless solid, mp 69-70 ° C, yield 73% of theory. ^{Χ Η} NMR δ (CDC1 _3): 1.33 (4H, m, 2 x CH _2), 1.47 to 1.6 (4H, m, 2 x CH _2), 2.56 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.93, 2.97 (1H, dd, J = 2.4, 15.2 Hz, H ₃ ), 3.22-3.24 (2H, m, NHCH ₂ ), 3 , 35, 3.39 (1H, dd, J = 5.2, 15.2 Hz, H ₃ ), 3.54, 3.72 (each 1H, d, J = 16.8 Hz, NCH ₂ ), 3.81 (1 H, s, _SCH2), 4.80 (1H, m,

Δ ₄ ), 6.11 (1H, m, NH), 7.05-7.36 (9H, m, 2.times.Ph-H); ⁼ +36.3 (c = 0.9% w / v in CHC1 ₃₎ at 25 ° C.

Determined Composition: 64.5% C, 6.5% H, 6.3% N, ^C 24 ^H 29 ^ClN 2 ° 2 ^S requires: 64.8% C, 6.6% H, 6.3% N.

Example 152

47 R, S 7 -N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

47 N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-isoazetidin-1-yl) acetamide (0.5 g) was reacted with (+) - (8, 8- Dichloro-camphorsulfonyl) oxaziridine (0.3 g) in dichloromethane (70 mL) at 25 ° C to give the title compound as a colorless solid after chromatography (silica / ethyl acetate), mp 159-160 ° C (0.21 g, to). ¹ H NMR δ (CDCl ₃ ): 1.3 to J = 7.6 Hz, PhCH ₂ ), 2.93, H ₃ ), 3.22 (2H, m, NHCH ₂ ), Hz, H ₃ ), 3.68, 4.13, 4.05 (each 1H, d, 6.65 (1H m, NH),

791 cm ¹ ;

[α] _D = - 166.91 (c = 1.08 • c.

Determined composition: C24H29ClN2O3 requires:, yield 83% of theoretical yield1.6 (8H,

2.98

3.44, each 1H,

J =

7.07

2.55 (2 H, t,

4.8, 14.8 Hz, J = 2.2, 14.8

3.88, (1H, m, H ₄ ), 2xPh-H), m, 4xCH ₂ ), (1H, dd, J = 3.48 (1H, dd, d, J = 17.4 Hz, NCH ₂₎ )

12.8 Hz, SOCH ₂ ), 4.50 to 7.40 (9H, m,% w / v in want ₃ ) at 25

N,

N.

Example 153

4S, SS-N- (6- (4-chlorophenyl) hexyl) - (4benzylsulphinyl-2-oxo-azetidin-l-yl) acetamide

4S-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulfinyl-2-isoazetidin-1-yl) acetamide (1 g) in dichloromethane (75 mL) was reacted at 25 ° C for 16 hours with ( -) - (8,8-Dichloro-camphenylsulfonyl) -oxaziridine (0.67 g) at 25 ° C to give the title product after chromatography (silica / ethyl acetate)

m.p. 159 DEG C. (0.95 g, 83% yield).

¹ H NMR δ (CDCl ₃ ): 1.2-1.6 (8H, m, 4xCH ₂ ), 2.55 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.93, 2, 98 (1H, dd, J = 4.8, 14.8 Hz, H ₃ ), 3.22 (2H, m, NHCH ₂ ), 3.44, 3.49 (1H, dd, J = 2.2 14.8 Hz, H ₃ ), 3.68, 4.13 (each 1H, d, J = 17.4 Hz, NCH ₂ ), 3.88, 4.05 (each 1H, d, J = 13 1 Hz, SOCH ₂ ), 4.50 (1H, m, H ₄ ), 6.65 (1H m, NH), 7.07 to 7.40 (9H, m, 2xPh-H), tc _{= 0} 1,791 cm ^-1 ;

[α] _D = + 169.2 (c = 1.0% w / v in CHCl ₃ ) at 25 ° C.

Assay Composition: 62.4% C, 6.3% H, 6.1% N, C 24 H 29 ClN 2 O 3 requires: 62.5% C, 6.3% H, 6.1% N.

Example 154

4R, SS-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Reaction of 47 N - (6- (4-chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide (0.59 g) with mCPBA (0.355 g / 65% purity) in dichloromethane ( 40 ml), as described in Example 30, the title compound is obtained as a colorless solid, m.p. 139 DEG-140 DEG C., after repeated recrystallization from butanone, the yield is 16% of theory.

* NMR δ (CDCl ₃ ): 1.33 (4H, m, 2xCH ₂ ), 1.5 to 1.65 (4H, m, 2xCH ₂ ), 2.56 (2H, t, J = 7), 6 Hz, PhCH ₂ ), 2.87, 2.91 (1H, dd,

J = 2.4, 15.6 Hz, H ₃ ), 3.16, 3.20 (1H, dd, J = 5.2, 15.6 Hz,

H ₃ ), 3.22-3.32 (2H, m, NHCH ₂ ), 3.87, 4.26 (each 1H, d, J = 16.8 Hz, NCH ₂ ) ··· 3.97, 4.18 (each 1H, d, J = 13.2 Hz,

SOCH ₂ ), 4.60 (1H, m-, H ₄ ), 7.08-7.41 (10H, m, 2xPh-H),

Tq_q 1,793 cm -1 · · · ·.

Determined: 61.6% C, 6.1% H, 6.1% N,

C24H29CIN2O3S.0,26H ₂ O requires: C 62.5%, H 6.3%, N 6.1%

Example 155

47 R, SS-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

N- (6- (4-Chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide (52.2 g) was treated with mCPBA (26.3 g / 65% -). purity) in dichloromethane (1500 mL) at -70 to -74 ° C for 120 minutes. After treatment with an aqueous solution of sodium sulfite and sodium bicarbonate, the organic layer was dried and evaporated to give a mixture of approximately 65:35 sulfoxides of diastereoisomers (2: 1) (53.1 g). This was combined with similarly obtained additional batches and separated by preparative HPLC on a Septech 800C using a 50 mm Merck Lichosphere 10 µm silica pack (220 g) as a stationary phase using a Merck 50 mm self-packed column and eluting with 60% ethanol / 40% n-hexane to give the title compound as a colorless solid, mp 139-140 ° C to 140 ° C, total yield 35% of theory.

[α] _D = + 169.2 (c = 1.0% w / v in CHCl 3) at 25 ° C. The @ ³ H NMR spectrum (CDCl3) was the same as in Example 154.

Determined composition: 62.5% C, 6.2% H, 6.2% N,

C24H29ClN2O3S requires: C 62.5%, H 6.3%, N 6.1%.

Example 156

47 R, SS-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

R - (+) - 1,1'-Binaphthol (0.256 g) was suspended in toluene (20 mL) at 25 ° C and Ti (OiPr) ₄ (0.134 mL) and water (0.168 mL) were added. After 1 hour, 47 N - (6 (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (2.07 g) in toluene (12 mL) was added and the mixture was stirred for 30 minutes. Tertiary butyl peroxide (1.36 mL) was then added and the mixture was stirred for 66 hours. Chromatography then gave a 6: 1 mixture of sulfoxides of diastereoisomers (47 R, SS: 47 R, S 7 R) (1.6 g, 75%). isomer

47 ?, S7? was removed by adding 0.222 g of 4S, SS-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide to the mixture, crystallizing racemate 47 ?, SS / 47 ?, SS from the mixture and crystallization of 47 R, SS-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide from the mother liquor (1.9

83 g (55% of theory) as a colorless solid (m.p. 139-140 ° C). The spectrum and physical properties were as described in Example 154.

Example 157

47 R, SS-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

(a) N - (-) (4-Benzylsulphinyl-2-oxoazetidin-1-yl) acetic acid

9.11 g of 7 - (-) - (4-benzylthio-2-oxoazetidin-1-yl) acetic acid was dissolved in 250 ml of dry dichloromethane and cooled to -70 ° C. Ozone gas was pulsed through the solution until starting material was consumed. The reaction mixture was then bubbled with oxygen and allowed to warm to room temperature. Triphenylphosphine (about 10 mg) was added to the solution. The solution was then evaporated to an oily solid (10.7 g). The resulting two-component mixture was then triturated with chloroform (100 mL) at room temperature to dissolve the oily portion. The solid was filtered off and found to consist predominantly of diastereoisomer 1 (47%, SZ) (4.55 g, 46%) (~ 90% of diastereoisomer 1), m.p. 142-144 ° C. The filtrate was then evaporated to dryness to give a glassy material, predominantly (94%) consisting of diastereoisomer 2 (47%, SS), melting point not determined.

^X H-NMR δ (CDC1 _3): 2.95 (1H, dd, ₃ H) ,, 3.29 (1 H, dd, H _3), 3.78 to 4.24 (4H, m, _NCH2, SOC ₂ ), 4.81 (1H, m, H ₄ ), 7.36 (5H, m, Ar-H).

b) To a mixture of 1-hydroxybenzotriazole (0.96 g), N, N'-bicyclohexylcarbodiimide (1.52 g) and acid predominantly 47 R, SS - (-) 4- (benzylsulfinyl-2-oxoazetidine-1-). yl) acetic acid (2 g), prepared in a), in dry dimethylformamide (50 mL) at room temperature was added 4-chlorophenylhexylamine (1.31 g, 0.0074 mol) in dry dimethylformamide. The reaction mixture was stirred for two hours. After treatment with water, evaporation of the organic solvents and recrystallization from ethyl acetate, the title compound was isolated in a 94: 6 mixture with the corresponding 4R, SR isomer (1.66 g, 55%). Melting point: 133-134 ° C.

Example 158

45, SR-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

The title compound was prepared from 4S-N- (6- (4-chloro-phenyl) -hexyl) - (4-benzylthio-2-oxoazetidin-1-yl) -acetamide as described in Example 156 but substituting R- (+) - 1,1'-binaphthol was used S - (-) - 1,1'-binaphthol and instead of 4S, SS-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1 - yl) acetamide was used 4R, SR-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide. The product was a colorless solid, mp 139-140 ° C, 44% yield.

¹ H NMR δ (CDCl ₃ ): 1.33 (4H, m, 2xCH ₂ ), 1.5-1.65 (4H, m, 2xCH ₂ ), 2.56 (2H, t, J = 7.7 Hz, PhCH ₂ ), 2.87, 2.91 (1H, dd, J = 2.4, 15.3 Hz, H ₃ ), 3.16, 3.20 (1H, dd, J = 5.1 15.3 Hz, H ₃ ), 3.22-3.32 (2H, m, NHCH ₂ ), 3.87, 4.26 (each 1H, d, J = 17.1 Hz, NCH ₂ ), 3.97, 4.18 (each 1H, d, J = 13 Hz, SOCH ₂ ), 4.60 (1H, m, H ₄ ), 7.08 to 7.41 (10H, m, 2xPh-H, NH); Tq_q 1793 cm ^-1 ; [α] _D = -124.11 (c = 1.1% w / v in CHCl ₃ ) at 25 ° C.

Determined composition: 62.4% C, 6.3% H, 6.1% N,

C ₂₄ H ₂ N ₁ O ₂ S requires: 62.5% C, 6.3% H, 6.1% N.

Example 159

4R-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphonyl-2-oxoazetidin-1-yl) acetamide

The title compound was chromatographically isolated from the reaction mixture prepared according to Example 156. The product was a colorless solid, mp 145 ° C, yield 18% of theory.

¹ H NMR δ (CDCl ₃ ): 1.3-1.6 (8H, m, 4xCH ₂ ), 2.56 (2H, t,

J = 7.6 Hz, -PhCH ₂ ), 2.96, 3.02 (1H, dd, J = 2.5, 15.4 Hz,

9 ₃ ), 3.09, 3.13 (each 1Η, d, J = 5.1, 15.4 Hz, H ₃ ), 3.24 (2H, m, NHCH ₂ ), 3.85, 3, 94 (each 1H, d, J = 16.9 Hz, NCH ₂ ), 4.34 (2H, dd, J = 14.2 Hz, SO ₂ CH ₂ ) 4.83 (1H, m, H ₄ ), 6.1 (1H, m, NH); 7.07-7.43 (9H, m, 2xPh-H); t _{c = Q} 1797 cm ^-1 ;

[α] P = - 34.71 (c = 1.0% w / v in CHCl ₃ ) at 25 ° C. Determined Composition: C 60.3%, H 6.0%, N 5.9%, ^C 24 ^H 29 ^ClN 2 ° 4 ^S requires: C 60.4%, H 6.1%, N 5.9%.

Example 160

4S-N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphonyl-2-oxoazetidin-1-yl) acetamide

The title compound was formed by reacting 4S-N (6- (4-chlorophenylhexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA as described in Example 4. The product was a colorless solid at temperature. 147 DEG C. The yield was 83% of theory.

^X H-NMR δ (CDC1 _3): 1.3 to

J = 7.6 Hz,

H ₃ ), 3.09, 3.12 (2H, m, NHCH ₂ ), NCH ₂ ), 4.34 (2H,

₄ H), 6.1 (1H, m,

798 cm ^-1 ; [a] _b in CHCl ₃ ) at 25 ° C.

Specified composition:

^ '24 ^Η 29 ^< ^ ¹ ^ 2θ4 ^ requires:

1.6 (8H, m, 4xCH _2),

PhCH ₂ ), 2.96, 3.03 (1H, dd, J = (each 1H, d, J = 5.1, 15.4

3.85, 3.94 (each 1H, d, J = 14.2 Hz, SO ₂ CH ₂ ), (9H, m,%

dd,

NH),. = +

7.08

36.3 = 14.2 to 7.43 (c = 1.1

6.0

6.1

2.56 (2H, t, 2.5, 15.4 Hz, Hz, H ₃ ), 3.25

J = 16.8 Hz,

4.83 (1 H, m, 2xPh-H); ^T C = O weight / volume

Example 161

4- R - (6-Phenylhexyl) - (4-benzylthio-2-oxoazetidin-1-yl) acetamide

The title compound was obtained by reaction of 4R- (4-benzylthio-2-oxo-azetidin-1-yl) acetic acid (Example 84) with dicyclohexylcarbodiimide and 6-phenylhexylamine as described in Example 29.

The product was a colorless solid, mp 46-47 ° C. The yield was 49% of the theoretical yield.

¹ H NMR δ (CDCl ₃ ): 1.33 (4H, m, 2xCH ₂ ), 1.5 to 1.65 (4H, m,

2xCH ₂ ), 2.59 (2H, t, J = 7.6 Hz, PhCH ₂ ), 2.92, 2.96 (1H, dd, J = 2.4, 15.2 Hz, H ₃ ), 3.22 (2H, m, NHCH ₂ ), 3.35, 3.39 (1H, dd, J = 5.2, 15.2 Hz, H ₃ ), 3.56, 3.71 (each 1H, d, J =

16.8 ^; Hz, NCH ₂ ), 3.81 (2H, s, SCH ₂ ), 4'80 (1H, m, H ₄ ), 6.0 (1H, m, NH), 7.15 to 7.4 (10H) , m, 2xPh-H); t _{c = Q} 1,776 cm ^-1 ;

[α] P = + 6.6 (c = 1.1% w / v in ethanol) at 25 ° C.

Determined composition: 70.0% C, 7.2% H, 6.9% N, 24.24, 30.22.22. Requires: 70.2% C, 7.4% H, 6.8% N.

Example 162

4R, SR-N- (6-Phenylhexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide

A mixture of (S) - (-) - 1,1'-bi-2-naphthol (28 mg, 0.98 mmol) in dry toluene (2 mL) was treated with titanium (IV) isopropoxide (14 mg, 0.0494 mmol). and water (25 mg, 1.34 mmol). The dark orange mixture was stirred for 60 minutes and then treated with a solution of RN- (6-phenylhexyl) (4-benzylthio-2-oxoazetidin-1-yl) acetamide (200 mg, 0.487 mmol) in dry toluene (1 mL). ). The reaction mixture was stirred for 30 minutes and further treated with tertiary butyl hydroperoxide (70% in water, 0.14 mL, 1.02 mmol) and stirring was continued for 3.5 hours. The product was purified by column chromatography using ethyl acetate to ethyl acetate / ethanol 15: 1 as eluents. Recrystallization from ethyl acetate gave the product as a pale yellow solid. The melting point of the product was 145 ° C. The yield was 0.079 g, 38% of theory.

¹ H NMR δ (CDCl ₃ ): 1.33 (4H, m, 2xCH ₂ ), 1.5-1.65 (4H, m, 2xCH ₂ ), 2.59 (2H, t, J = 7.8) Hz, PhCH ₂ ), 2.93, 2.97 (1H, dd, J = 4.8, 14.8 Hz, H ₃ ), 3.22 (2H, m, NHCH ₂ ), 3.45, 3 48 (1H, dd, J = 2.4, 14.8 Hz, H ₃ ), 3.70, 4.12 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 3.88, 4.06 (each 1H, d, J = 12.8 Hz, S0CH _2), 4.50 (1 H, m, H _4), 6.65 (1 H, m, NH), .7,16 to 7, Δ (10H, m, 2xPhH); Xq_q = 1,789 cm ^-1 .

Determined Composition: C 65.7%, H 6.7%, N 6.3%, ^C 24 ^H 30 ^N 2 ° 3 ^S requires: C 67.6%, H 7.1%, N 6.6%.

Example 163

N- (6- {4-Fluorophenyl} hexyl) -4- (4-allyloxycarbonyl-benzylthio-2-oxoazetidin- 1-yl) acetamide

Reaction of 4- (4-allyloxycarbonylbenzylthio) azetidin-2-one with N- (6- (4-fluorophenyl) hexyl-1-bromoacetamide) as described in Example 85a afforded the title compound

in the form of a colorless oil;

^X H-NMR δ (CDC1 _3): 1 J = 7.6 Hz, CH ₂ Ph),

₃ H), 3.23 (2H, m,

15.4 Hz, H ₃ ), 3.53,

3.86 (2H, s, _{SCH2), CH2-CH),} 6.0 (2H,

7.10 (2 H, m, 4-FPh-H),

4-CO ₂ allylPh-H), 8.02 (2H,

The yield was 43% teorenhch ₂ ),

3.78

4.83 m, NH, 30-1.60 (8H,

2.90, 2.97 (1H,

3.35, (each 1H, (3H, m, CO ₂ CH ₂ ,

_CH2-CH), 6.94

7.39 (2H, d, m, 4xCH _2), 2.55 (2H, t, dd, J

3.41 d, J = 2.4, 15.4 Hz, (1H, dd, J = 5.1, = 16.6 Hz, NCH ₂ ),

H ₄ ), 5.37 (2H, m, (2H, m, 4-FPh-H), d, J = 8.3 Hz,

J = 8.3 Hz, 4-CO ₂ allylPh-H).

Treatment of N- (6- (4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA followed by recrystallization as described in Examples 2 and 3 afforded the compounds described in Examples 164 and 165.

Example 164

N- (6- {4-Fluorophenyl}) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1)

Colorless solid. Mp 190-191 ° C. The yield was 24% of the theoretical yield.

^X H-NMR δ (CDC1 _3): 1.30 and 1, 60 (8H, m, 4xCH _2), 2.55 (2H, t, J = 7.6 Hz, _CH2 Ph), 2.95, 2 98 (1H, dd, J = 4.8, 14.8 Hz)

H ₃ ), 3.24 (2H, m, NHCH ₂ ), 3.42, 3.46 (1H, dd, J = 2.4, 14.8

Hz, H ₃ ), 3.76, 4.09 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 3.95, 4.01 (each 1H, d, J = 13.2 Hz, SOCH ₂ ), 4.59 (1H, m, H ₄ ) 4.84 (2H, m, CO ₂ CH ₂ ), 5.37 (2H, m, CH ₂ = CH), 6.0 (1H, m CH ₂ = CH, 6.47 (1H, m, NH), 6.95 (2H, m, 4-FPh-H), 7.10 (2H, m, 4-FPh-H), 7, 36 (2H, d, J = 8Hz, 4-CO ₂ allylPh-H), 8.09 (2H, d, J = 8Hz, 4-CO ₂ allylPh-H).

Determined composition: 63.3% C, 6.2% H, 5.4% N, ^C 28 ^H 33 ^FN 2 ° 5 ^ requires:

63.6% C, 6.3% H, 5.3% N.

Example 165

N- (6- {4-Fluorophenyl} hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Colorless solid. Mp 115-117 ° C. The product yield was 53% of the theoretical yield.

^X H-NMR δ (CDC1 _3): 1.30 -1.60 (8H, m, 4xCH _2), 2.56 (2H, t, J = 7.6 Hz, _CH2 Ph), 2.91, 2 95 (1H, dd, J = 2.4, 15.2 Hz)

H ₃ ), 3.27 (3H, m, NHCH ₂ , H ₃ ), 3.94, 4.22 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 4.04, 4.18 (each 1H, d, J = 12.8 Hz,

SOCH ₂ ), 4.65 (1H, m, H ₄ ), 4.84 (2H, m, CO ₂ CH ₂ ), 5.37 (2H, m, CH ₂ = CH), 6.0 (1H, m, CH ₂ = CH), 6.95 (3H, m, 4-FPh-H, NH),

7.10 (2H, m, 4-FPh-H), 7.36 (2H, m, 4-CO ₂ allylPh-H), 8.09 (2H, m, 4-CO ₂ allylPh-H). t _{c = 0} = 1795 cm ^-1 .

Determined composition: 63.5% C, 6.2% H, 5.4% N,

C28H33FN2O5S requires C 63.6% H 6.3% N 5.3%

Example 166

N- (6- (4-Fluorophenyl) hexyl) -4- (4-carboxybenzylsulphinyl-2-isoazetidin-1-yl) acetamide (diastereoisomer 2)

A solution of N- (6- {4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) (0.35 g, 0.662 mmol), triphenylphosphine (0.18 g) , 0.686 mmol) and tetrakis (triphenylphosphine) palladium (22 mg) were treated with a solution of pyrrolidine (0.048 g, 0.675 mmol) in dry dichloromethane (1 mL). The reaction mixture was then stirred for 22 hours. The product was purified by column chromatography using dichloromethane, 1: 1 dichloromethane / acetone, 50: 50: 1 dichloromethane / acetone / glacial acetic acid as eluents, followed by washing with dichloromethane and ether. A solid colorless product was obtained. Mp 185-186 ° C. The yield was 67% of the theoretical yield.

¹ H NMR δ (DMSO): 1.26 (4H, m, 2xCH ₂ ), 1.38 (2H, m, CH ₂ ),

1.50 (2H, m, _CH2), 2.96, 2.99 (1H, dd, J = 2, 15.2 Hz, H _3),

3.06 (2Η, m,

NCH ₂ ), 4.13 (1H, m, H ₄ ),

NHCH ₂ ), 3.84, 4.09 (each 1H, d, J = 17.2 Hz, 4.31 (each 1H, d, J = 12.8 Hz, SOCH ₂ ), 4.84 7.05 (2H, m, 4-FPh-H), 7.19 (2H, m, 4-FPh-H),

7.47 (2H, d, J = 8Hz, 4-CO ₂ allylPh-H),

7.93 (2 H, d, J = 8)

CO ₂ allylPh-H), 8.10 (1H, m, NH), 13 (1H, broad s, CO ₂ H).

Determined composition: C 60.9, H 5.9, N 5.7,

C ₂₃ H ₂ FF ₂ O ₃ S.0.136H ₂ O requires: 61.2% C, 6.0% H, 5.7% N.

Example 167

N- (6- {4-Fluorophenyl} hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

To a solution of N- (6- (4-fluorophenyl) hexyl) -4- (4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (0.3 g, 6 mmol) in N-methyl-pyrrolidin-2-one Anhydrous potassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.9 g, 5 mmol) were added (4 mL). The mixture was stirred at room temperature for 18 hours, then treated with brine and extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography using a) ethyl acetate and b) ethyl acetate / methanol (95: 5) as eluents. Evaporation of the appropriate fractions gave the title compound as a white powder (0.3 g, 75%). The melting point of the product was

119 C.

¹ H NMR δ (CDCl ₃ ): 1.33-1.41 m), 2.56 (2H, t, J = 7.5 Hz),

Hz), 3.15-3.40 (3H, m), 3.93

Hz), 4.30 and 4.22 (each 1H,

5.25 (1H, m), 6.86-7;

m).

Specified composition:

C28H35FN2O5S requires:

d, (5H,

63.05

63.38% C, (10H, m), 1.45-1.58 (4H,

2.92 (1H, dd, J = 2.5, 15.4 and 4.24 (each 1H, d, J = 18)

J = 15 Hz), 4.69 (1H, m), m), 7.35 (2H, m), 8.07 (2H,% C, 6.46% H, 5.24% N,

H, 6.65; N, 5.24.

The following compounds (Examples 168, 169) were prepared in a similar manner.

Example 168

- 90 N- (6- (4-Fluorophenyl) hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Cream-colored solid. The yield was 68% of the theoretical yield.

^X H-NMR δ (CDC1 _3): 1.03 (3H, t, J = 7.4 Hz, _CH2), 1.30 and

1.60 (8H, m, 4xCH ₂ ), 1.80 (2H, m, CH ₂ CH ₃ ) 2.56 (2H, t, J =

7.6 Hz, CH ₂ Ph), 2.90, 2.94 (1H, dd, J = 2.4, 15.6 Hz, H ₃ ),

3.22 (3H, m, NHCH ₂ , H ₃ ), 3.94, 4.22 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 4.04, 4.18 (each 1H, d, J = 12.8 Hz, _SOCH2),

4.30 (2H, t, J = 6.6 Hz, CO ₂ CH ₂ ), 4.65 (1H, m, H ₄ ), 6.95 (3H, m, 4-FPh-H, NH), 7.10 (2H, m, 4-CO-H), 7.36 (2H, m, 4-CO- _2- propylPh-H), 8.07 (2H, m, 4-CO- _2- propylPh-H); ^T c = O ⁼

795 cm ¹ .

Determined composition: 62.4% C, 6.4% H, 5.3% N,

C28H35FN2O5S.1% _H2O requires: 62.7% C, 6.7% H, 5.2% N.

Example 169

N- [6- (4-Fluorophenyl) hexyl] - [4- (4-ethyloxycarbonylbenzyl) sulfinyl-2-oxo-azetidin-1-yl] acetamide (diastereoisomer 2)

Solid, almost white. The yield of the product was 82% of the theoretical yield. Mp 130-131 ° C.

¹ H NMR δ (CDCl ₃ ): 1.3-1.6 (1H, m), 2.55 (2H, t), 2.91 (1H, dd), 3.25 (1H, dd), 3 27 (2H, m), 3.94 and 4.23 (each 1H, d, J = 20 Hz), 4.17 and 4.02 (each 1H, d, J = 12.5 Hz), 4, 39 (2H, q), 4.65 (1H, dd), 7.01 (5H, m), 7.35 and 8.07 (each 2H, d, J = 8.27 Hz).

Determined: 62.6% C, 6.3% H, 5.4% N,

C29H33FN2O5S requires:. % C, 62.8;% H, 6.4;

Example 170

N- (6- [4-Fluorophenyl] hex-l-yl) -4-carboxybenzylthio) -2-oxo-azetidin-l-yl-acetamide

Reaction of N-6- [4-fluorophenyl] hex-1-yl) -4-allyloxycarbonylbenzylthio) -2-oxoazetidin-1-yl acetamide under the conditions described in Example 166 afforded the title compound as a colorless oil. The yield of product was

62% of theory. (4H, ^{Χ Η} NMR δ (CDC1 ₃₎ 1.24 (4H, m) 1.41 to 1.51 width m, 2.50 (3H, t, J = 7.4Hz), 2.87 to 2.93 (1 H, broad dd), 3.09 up to 3.47 (4H, m) 3.6 to 4 3.80 (3H, m) 4.86 (1H, broad m), 6.75 (1H, broad m), 6, 86 to 6.96 (2 H, m), 7.03 to 7.09 (2H, m), 7.26 (2H, m), 7.97 (2H, m),

Example 171

N- (6- [4-Fluorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylthio) -2-oxoazetidin-1-ylacetamide

N- (6- [4-fluorophenyl] hex-1-yl) - (4-carboxybenzylthio) -2-oxoazetidin-1-ylacetamide (1 g, 2.1 mmol) was dissolved in dry dichloromethane (5 mL). and the solution was treated with a solution of trimethylsilyldiazomethane (6 mL of a 2M solution in hexane) with stirring for 3 hours. The solvent was removed and the residue was chromatographed on silica using dichloromethane: methanol (9: 1) as the eluting solvent. Evaporation of the appropriate fractions gave the title compound as an oil (0.27 g, 26%).

^X NMR δ: 1.32 (4H, bm), 1.4 to 1.7 (4H, bm), 2.56 (3H, t, J = 7.4 Hz): 2.9 (1H, dd J = 2.5, 15.3 Hz), 3.15-3.35 (3H, m), 3.4-4.0 (7H, m), 4.86 (1H, m,), 5 99 (1 H, bm),

6.90 to 6.98 (2H, m), 7.07 to 7.13 (2H, m), 7.40 (2H, m),

7.97 (2 H, m).

Example 172

N- [6- (4-Fluorophenyl) hexyl] - [4- (4-methyloxycarbonylbenzyl) sulfinyl-2-oxo-azetidin-1-yl] acetamide (diastereoisomer 2)

Reaction of N- (6- [4.-fluorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylthio) -2-oxoazetidin-1-ylacetamide with mCPBA as described in Examples 2 and 3 affords the title compound: said compound as a waxy solid. The yield was 26% of the theoretical yield.

^{Χ Η} NMR δ: 1.34 (3H, bm) 1.4 to 1.7 (4H, m), 1.55 1.70 (4H, m), 2.50 (3H, t), 2. 95 (1H, dd), 3.15-3.3 (3H, m),

3.9-4.3 (7H, m), 4.6 (1H, m), 6.94 (2H, t), 7.12 (2H, t),

7.36 (2H, d), 8.06 (2H, d);

Specified composition:

tQ_Q = 1795 cm ^-1 ,

61.72% C, 6.17% H, 5.5% N, 31 ^ 26 ^{Β Β} ^ ^ 2θ5 requires 62.13% C, 6.22% H, 5.6% N.

Example 173

N- (6- (4-Chlorophenyl} hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Reaction of N- (6- {4-chlorophenyl} hexyl) -4- (4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereomer 2) (Example 130) with isopropyl iodide as in Example 169 gave the title compound. the title compound in the form of white crystals. The yield was 78% of the theoretical yield.

The melting point of the product was 114.5

Found: C 61.45, H 6.35, N 5.26,

C28H35ClN2O5S requires C 61.47% H 6.45% N 5.12%.

Example 174

N- (6- {4-Chlorophenyl}) hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Reaction of N- (6- {4-chlorophenyl) hexyl) -4- (4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) (Example 130) with n-propyl iodide as described in Example 169 affords the title compound: m.p. compound in the form of a white powder. The yield was 69% of the theoretical yield. Mp 104 ° C.

^X H-NMR δ (CDC1 _3): 1.03 (3H, t, J = 7.4 Hz), 1.36 (4H, m), 1.55 (4H, m), 1.81 (2H, m 1.56 (2H, t, J = 7.9 Hz), 2.89 (1H, dd, J = 2.5, 15.3 Hz), 3.23 (3H, m), 3.90 and 4.16 (each 1H, d, J = 17.1 Hz), 4.00 and 4.27 (each 1H, d, J = 12.9 Hz), 4.32 (t, J = 7.4 Hz), 4.63 (1H, m), 7.01 (1H, bm), 7.06 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz).

Example 175

N- (6- {4-Chlorophenyl} hexyl) -4- (4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Reaction of N- (6- (4-chlorophenyl) hexyl) -4- (4-carboxybenzyl)

sulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) (Example 130) with ethyl iodide, as described in Example 169, gave the title compound as a white powder. The yield was 70% of the theoretical yield. Mp 124 ° C.

^{Χ Η} NMR δ (CDC1 _3): 1.33 (4H, m), 1.40 (3H, t, J = 7.1 Hz);

1.55 (4H, m), 2.56 (t, J = 7.4 Hz), 2.88 (1H, dd, J = <2,

17.7 Hz), 3.19-3.27 (3H, m), 3.90 and 4.19 (each 1H, d,

J = 17.1), 4.01 and 4.16 (each 1H, d, J = 02.9 Hz), 4.35 (2H, q, J = 7.2 Hz), 7.01 (1H, bm), 7.06 (2H, d, J = 8.4)

Hz), 7.24 (2H, d, J = 8.4Hz), 7.34 (2H, d, J = 8.3Hz),

8.05 (2H, d, J = 8.3Hz).

Example 176

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) thio-2-oxoazetidin-1-yl] acetamide

Treatment of 4- (4- (allyloxycarbonylmethyl) benzylthio) azetidin-2-one with N- (6- (4-fluorophenyl) hexyl) -1-bromoacetamide, as described in Example 85a, afforded the title compound as a colorless oil. The yield was 16% of the theoretical yield.

^{Χ Η} NMR δ (CDC1 _3): 1.30 -1.60 (8H, m), 2.56 (2H, t), 3.00 2.95 (1 H, dd), 2.97 and 3. 57 (each 1H, dd), 3.23 (1H, m),

3.42 (1H, dd), 3.65 (2H, s), 3.77 (2H, q), 4.59 (2H, m),

4.88 (1H, dd), 5.23-5.32 (2H, m), 5.9 (1H, m), 6.1 (1H, m,

t), 6.9-7.30 (8H, m).

Reaction of N- (6- (4-fluorophenyl) hexyl) -4- (4- (allyloxycarbonylmethyl) benzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA followed by recrystallization as described in the Examples 2 and 3, the compounds described in Examples 178 and 179 were obtained.

Example 177

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereomer 1)

White crystalline substance. The yield was 16% of the theoretical yield. Melting point: 132-133 ° C.

Determined composition: 63.3% C, 6.3% H, 5.0% N, ^C 29 ^H 35 ^FN 2 ° 5 ^S - 5 ° ^5H 2 ° requires: 63.2% C, 6.6% H, 5,1% N.

Example 178

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl Jacetamide (Diastereoisomer 2) White crystalline solid. The yield was 56% of the theoretical yield. Mp 106-109 ° C.

Determined Composition: 64.2% C, 6.4% H, 5.1% N, ^C 29 ^H 35 ^FN 2 ° 5 ^S requires: 64.2% C, 6.4% H, 5.2% N.

Example 179

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) thio-2-oxoazetidin- l-yl] -acetamide

Reaction of N- [6- (4-fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) -benzyl) thio-2-oxo-azetidin-1-yl] acetamide under conditions as described in Example 166 gave the title compound as a white solid. The yield was 87% of the theoretical yield.

¹ H NMR δ (CDCl ₃ ): 1.21 (4H, m), 1.45 (2H, m), 1.58 (4H, m),

2.56 (2H, t, J = 7.6 Hz), 2.84 and 3.47 (each 1H, d, J =

16.9 Hz), 2.90 (1H, dd, J = <16.6 Hz), 3.14 (2H, m),

3.39 (1H, dd, J = 5.3, 15.1 Hz), 3.64 (2H, s), 3.69 (2H, dd, J = 7.7, 14.3 Hz), 4 86 (1H, m), 6.29 (1H, bm), 6.91-7

7.26 (8 H, m).

Example 180

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) sulfinyl-2-oxo-azetidin-1-yl] acetamide (diastereoisomer 1)

A solution of N- [6- (4-fluorophenyl) hexyl] - [4- (4- (carboxymethyl) -benzyl) -thio-2-oxo-azetidin-1-yl] -acetamide (1,5g, 3 mmol) in dichloromethane (100ml) at -78 ° C was bubbled with ozonated oxygen until the light blue color persisted. Nitrogen was then bubbled through the reaction mixture, allowed to warm to room temperature and evaporated to dryness. The residue was crystallized from ethyl acetate to give the title compound (0.49 g, 33%). The melting point of the product was

160 to 161 ’C.

¹ H NMR δ (DMSO-d ₆ ): 1.26 (4H, m), 1.38 (2H, m), 1.5.3 (2H,

m), 2.54 (2H, t, J = 7.6Hz), 3.04 (3H, m), 3.14 (1H, dd,

J = 1.6,> 12 Hz), 3.57 (2H, s), 3.57 and 4.00 (each 1H, d,

J = 21.6 Hz), 3.80 and 4.10 (each 1H, J = 13.2 Hz), 4.89 (1H, m), 7.05 to 7.26 (8H, m), 7 98 (1H, bm), 12.3 (1H, bs).

Example 181

N- [6- (4-Fluorophenyl) hexyl] - [4- (4- (carboxymethyl) -benzyl) sulfinyl-2-oxo-azetidin-1-yl] acetamide (diastereoisomer 2) Evaporation of the filtrate to give diastereomer 2 , z (65:35) (0.31 g, 20% mp of the product was 125 and ¹ H NMR δ (DMSO-d ₆ ): 1.26 (4H,

m), 2.55 (2H, m), 2.91 (1 H, dd, J (2H, m), 3.29 (LH, m), 3.57 (2 H, s), 4.82 (LH, m), 7.05 to 7.29 (8H, m); (1 H, bs).

'C

1.37 (2H, m), 1.51 (2H, = 2.4, 15.2 Hz), 3.06

3.99 to 4.21 (4H, m),

8.13 (1 H, bm), 12.32

Example 182

N-2,4-Dichlorobenzyl- (4-benzylthio-2-oxo-azetidin-l-yl) -acetamide

Treatment of (4-benzylthio-2-oxoazetidin-1-yl) acetic acid with 2,4-dichlorobenzylamine under the conditions of Example 86 afforded the title compound as a colorless solid, m.p. 132-133. C. Yield of the product was 72% of the theoretical yield.

^{Τ Η} NMR δ (CDC1 _3): 2.93, 2.97 (1 H, dd, J = 2.4, 15.4 Hz,

H ₃ ), 3.36, 3.39 (each 1H, d, J (2H, m, NHCH ₂ )), (1H, dd, J = 5.2, = 16.9 Hz, NCH ₂ ), 4, 80 (1 H, m, H ₄ ),

15.4 Hz, H ₃ ), 3.56, 3.70

3.76 (2H, s, _SCH2), 4.47

6.5 (1H, m, NH), 7.20-7

7.34 (7H, m, Ph-H, 2,4-diClPh-H),

2,4-diClPh-H); x _{c = 0} 1776 cm ¹ .

7.38 (1 H, d, J = 2 Hz,

, The composition: 55.8% C, 4.5% H, 6.9% N ^ '19 ^ 18 ^{<^ 1} ^ 2 2θ2® requires 55.8% C, 4.4% H, 6.8 % N.

Treatment of N-2,4-dichlorobenzyl- (4-benzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA followed by recrystallization as described in Examples 2 and 3 gave the compounds described in Examples 183 and 184. Reaction N-2,4 -dichlorobenzyl (4-benzylsulfinyl-2-oxoazetidin-1-yl) -acetamide with mCPBA applies to Example 185.

Example 183

N-2,4-Dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1)

Colorless solid, m.p. 224-226 ° C, 16% yield.

^X H-NMR δ (DMSO): 3.03, 3.07 (1 H, dd, J = 4.8, 14.8 Hz, H _3), 3.15, 3.18 (1H, dd, J = 1 Δ, 14.8 Hz, H ₃ ), 3.78, 4.16 (each 1H, d,

J = 16.8 Hz, NCH ₂ ), 3.85, 4.14 (each 1H, d, J = 12.8 Hz, SOCH ₂ ), 4.33 (2H, d, J = 5.6, 20) Hz, NHCH ₂ ), 4.93 (1H, m, H ₄ ), 7.32-7.42 (7H, m, Ph-H, 2,4-diClPh-H), 7.61 (1H, d J = 2 Hz, 2,4-diClPh-H), 8.62 (1H, m, NH).

, The composition: 51.7% C, 4.2% H,% N .6,4, ^ 19 ^ 18 ^ 2 ^ ^Χ 2θ3® requires 53.7% C, 4.3% H, 6.6% N.

Example 184

N-2,4-Dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Colorless solid, mp 162-163 ° C, yield 45% of theory.

^X H-NMR δ (DMSO): 2.91, 2.95 (1H, dd, J = 2.2, 15.4 Hz, H _3), 3.30 (1 H, m, ₃ H), 3.97 4.21 (each 1H, d, J = 17.2 Hz,

NCH ₂ ), 4.05, 4.20 (each 1H, d, J = 12.8 Hz, SOCH ₂ ), 4.34 (2H, d, J = 5.8 Hz, NHCH ₂ ), 4.83 (1H, m, H ₄ ), 7.32-7.42 (7H, m, Ph-H, 2,4-diClPh-H), 7.60 (1H, d, J = 2 Hz,

2,4-diClPh-H), 8.72 (1 H, m, NH), t _{c =} 793 cm _Q1 ^first

, The composition: 53.5% C, 4.4% H, 6.6;% N, C _{1 GH-L} gcl ₂ N ₂ O ₃ S requires: 53.7% C, 4.3% H, 6.6 % N.

Example 185

N-2,4-Dichlorobenzyl- (4-benzylsulphonyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, m.p.

163-164 ° C, the product yield was 77% of the theoretical yield.

³ H NMR δ (DMSO): 3.08 (1H, m, m ₃ ), 3.30 (1H, m, H ₃ ), 3.77, 4.19 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 4.34 (2H, m, NHCH ₂ ,), 4.66, 4.77 (each 1H, d, J = 13.4 Hz, SO ₂ H ₂ ), 5.09 (1H , m, H ₄ ), 7.38 (7H, m, Ph-H, 2,4-diClPh-H), 7.62 (1H, m,

2,4-diClPh-H), 8.67 (1 H, m, NH), t _{c =} 796 cm _Q1 ^first

Determined Composition: C 51.5%, H 4.1%, N 6.3%, ^C 19 ^H 18 ^Cl 2 ^N 2 ° 4 ^S requires: C 51.7%, H 4.1%, 6.4% N.

Example 186

N-3,4-Dichlorobenzyl- (4-benzylthio-2-oxoazetidin-1-yl) acetamide.

Treatment of (4-benzylthio-2-oxoazetidin-1-yl) acetic acid with 3,4-dichlorobenzylamine under the conditions of Example 86 afforded the title compound as a colorless solid, m.p. 90-91 ° C. , the product yield was 68% of the theoretical yield.

^{Χ Η} NMR δ (CDC1 ₃₎ :, 2.94, 2.98 (1H, dd, J = 2.4, 15.6 Hz, ₃ H), 3.36, 3.39 (1 H, dd, J = 5.2, 15.6 Hz, h ₃ ) , 3,62, 3.70 (each 1H, d, J = 16.8 Hz, _H2); 3.79 (2H, with, sch ₂ ), 4.38 (2H, m, NHCH ₂ ) 4.80 (1 H, m, H ₄ ) 6.5 (1H, m, NH), 7.12 (1H, m, 3,4-) diCIPh-H); 7.26 to 7.40 (7 H, m. Ph-H 3,4-diClPh-H), ^T = 0 ^1,778 cm ¹ . Fixed Ingredients: 55.8% C, 4.5% H, 6.9 % N, ^C 19 ^H 18 ^Cl 2 ^N 2 ° 2 ^N requires: 55.8% C, 4.4% H, 6.8 % N.

Reaction of N-3,4-dichlorobenzyl- (4-benzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA followed by recrystallization as described in Examples 2 and 3 affords compounds described in Examples 187 and 188. Reaction N-3, 4-Dichlorobenzyl (4-benzylsulphinyl-2-oxoazetidin-1-yl) -acetamide with mCPBA gave the compound of Example 189.

Example 187

N-3,4-Dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1)

Colorless solid, m.p. 213 DEG-214 DEG C., yield 14% of theory.

¹ H NMR δ (DMSO): 3.03, 3.06 (1H, dd, J = 4.4, 14.8 Hz, H ₃ ), 3.15, 3.18 (1H, dd, J = 2) 14.8 Hz, H ₃ ), 3.78, 4.14 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 3.85, 4.14 (each 1H, d, J =

12.8 Hz, SOCH ₂ ), 4.29 (2H, d, J = 6 Hz, NHCH ₂ ), 4.93 (1H, m,

H ₄ ); 7.25 (1H, m, 3,4-diClPh-H), 7.31-7.40 (5H, m,

Ph-H), 7.52-7.56 (2H, m, 3,4-diClPh-H), 8.62 (1H, m, NH).

Designed for: 53.0% C, 4.3% H, 6.5% N, ^ 19 ^ 18 ^ ³ 2 ^ 2θ3 ³ requires: 53.7% C, 4.3% H, 6.6% N .

Example 188

N-3,4-Dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2)

Colorless solid, m.p.

155-156 ° C, yield of product was 33% of theoretical.

^X H-NMR δ (DMSO): 2.91, 2.95 (1H, dd, J = 2.2, 15.3 Hz, H _3), 3.30 (1 H, m, ₃ H), 3.96 4.18 (each 1H, d, J = 17.2 Hz, NHCH ₂ ), 4.05, 4.20 (each 1H, d, J = 12.8 Hz, SOCH ₂ ), 4.31 (2H , d, J = 5.9 Hz, NHCH ₂ ), 4.83 (1H, m, H ₄ ), 7.27 (1H, m,

3,4-diClPh-H), 7.31-7.37 (5H, m, Ph-H), 7.54-7.57 (2H, m, 3,4-diClPh-H), 8.72 (1H, m, NH), tc _{= Q} 1795 cm ^-1 .

Determined composition: 53.7% C, 4.3% H, 6.5% N, 1919 ^ 18 ^<33 2 ^ 2θ3 ³ requires: 53.7% C, 4.3% H, 6.6% N.

Example 189

N-3,4-Dichlorobenzyl- (4-benzylsulfonyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, m.p. 173-174 ° C, yield 86%.

¹ H NMR δ (DMSO): 3.08 (1H, m, H ₃ ), 3.30 (1H, m, H ₃ ), 3.76, 4.18 each 1H, d, J = 17.2 Hz NCH ₂ ), 4.31 (2H, d, J = 5.9 Hz, NHCH ₂ ), 4.66, 4.77 (each 1H, d, J = 13.4 Hz, SO ₂ CH ₂ ),

5.09 (1H, m, H ₄ ), 7.27 (1H, m, 3,4-diClPh-H), 7.38 (5H, s, Ph-H), 7.53-7.59 ( 2H, m, 3,4-diCl (Ph-H), 8.66 (1H, m, NH).

Determined Composition: C 51.6%, H 4.2%, N 6.4%, C 19 H 18 Cl 2 N 2 O 4 S requires: C 51.7%, H 4.1%, N 6.4%.

Example 190 (3S, 4R) -N- (6- {4-Fluorophenyl} hexyl) - (3-chloro-4-benzylthio-2-oxoazetidin-1-yl) acetamide

(a) (3S, 4R) - (4-Benzylthio-3-chloro-2-oxoazetidin-1-yl) -acetic acid

A suspension of methyl [(3S, 4R) -4-benzylthio-3-chloro-2-oxoazetidin-1-yl) acetate (2.87 g, 0.00957 mol) (Example 305) in methanol (50 mL) was cooled to 10 ° C and aqueous 1 M sodium hydroxide solution (9.6 mL) was added over 40 minutes. The cooling bath was discarded and the reaction mixture was stirred for 30 minutes, evaporated to remove methanol, diluted with water and washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and extracted (2x) with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO ₄ ) and evaporated to an oily consistency. Precipitations from ether-petroleum ether gave the product as a colorless solid (1.15 g, 42%), mp 132-134 ° C.

b) (3S, 4R) -N- (6- {4-Fluorophenyl} hexyl) - (3-chloro-4-benzylthio-2-oxoazetidin-1-yl) acetamide

Treatment of (3S, 4R) - (4-benzylthio-3-chloro-2-oxoazetidin-1-yl) acetic acid with 6- (4-fluorophenyl) hexylamine under the conditions described in Example 86 afforded the title compound colorless oil. yield

100 of the product was 85% of the theoretical yield.

^{Χ Η} NMR δ (CDC1 _3): 1.3 to 1.6 (8H, m, 4xCH _2), J = 7.6 Hz, _CH2 Ph), 3.22 (2H, m, NH CH ₂₎ 3, 51

1 H, d, J = 16.5 Hz, _NCH2), 3.83 (2H, s, _SCH2);

J = 1.7 Hz, H ₄ ), 4.79 (1H, d, J = 1.7 Hz, H 3), NH), 6.95 (2H, m, 4-FPh-H), (2H, m, 4-FPh-H),

2.56 (2 H, t,

3.81 (each

4.58 (1 H, d. 5 80 (1 H, m. 7 30 (5H, m.

Ph-H).

Reaction of (3S, 4R) -N- (6- (4-fluorophenyl) hexyl) - (3-chloro-4-benzylthio-2-oxoazetidin-1-yl) acetamide with mCPBA under the conditions described in Examples 2 and 3 afforded the compounds described in Examples 191 and 192.

Example 191 (SR, 3S, 4R) -N- (6- (4-Fluoro-phenyl) -hexyl) - (3-chloro-4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, m.p. 135 DEG-136 DEG C., yield 18% of theory.

^{Χ Η} NMR δ (CDC1 _3): 1.3-1.6 (8H, m, 4xCH _2), 2.56 (2H, t, J =

7.8 Hz, CH ₂ Ph), 3.22 (2H, m, NH CH _2), 3.80, 4.13 (each 1H, d, J = 17.2 Hz, _NCH2), 4.08, 4.23 (each 1H, d, J = 13.2 Hz, SOCH ₂ ), 4.67 (1H, d, J = 1.6 Hz, H ₄ , 5.38 (1H, d, J = 1, 6 Hz, H ₃ ), 6.47 (1 H, m, NH), 6.95 (2 H, m, 4-FPh-H), 7.10 (2 H, m, 4-FPh-H), 7, 39 (5H, m, Ph-H) x? q ₌ 1808 ^cm-1. [a] p in ° C = - 117.4 ° (0.973% w / v CHC1 _3).

Assay Composition: 60.1% C, 5.8% H, 5.9% N, ^C 24 ^H 28 ^ClFN 2 ° 3 ^S requires: 60.2% C, 5.9% H, 5.9% N.

Example 192 (SS, 3S, 4R) -N- (6- (4-Fluoro-phenyl) -hexyl) - (3-chloro-4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide

Colorless solid, m.p. 88 DEG-89 DEG C., yield 52%. ^X H-NMR δ (CDC1 _3): 1.3 to 1.6 (8H, m, 2 x CH _2), 2.56 (2H, t,

J = 7.6 Hz, _CH2 Ph), 3.26 (2H, m, NH CH _2), 3.92, 4.28 (each 1H, d, J = 17.2 Hz, _NCH2), 4, 10, 4.18 (each 1H, d, J =

101

13.2 Hz, SOCH ₂ ), 4.65 (1H, d, J = 2Hz, H ₃ ), 4.72 (1H, d, J = 2Hz, H ₃ ), 6.95 (2H, m 4-FPh-H), 7.09 (1 H, m, NH),

7.10 (2H, m, 4-FPh-H), 7.39 (5H, m, Ph-H), t _{c = 0} 1 809 cm ^1st

[α] _D at 25 ° C = + 75.3 ° (0.908% w / v CHCl ₃ ).

Determined Composition: C 60.2%, H 5.9%, N 5.9%, ^C 24 ^H 28 ^ClFN 2 ° 3 ^S requires: C 60.2%, H 5.9%, N 5.9%.

Example 193

N- (6- (4-fluorophenyl) hexyl) - (3 S, 4 R) -4-benzylthio-3 - ((R) hydroxyethyl) -2-oxo-azetidin-l-yl-acetamide

a) (3S, 4R) -4-Benzylthio-3 - ((R) - (t-butyldimethylsilyloxy) ethyl) -2-azetidinone

Reaction of (3R, 4R) -4-acetoxy-3 - ((R) - (t-butyl-dimethylsilyloxy) ethyl) -2-azetidinone with sodium benzylthiolate as described in Example 1a affords the title compound. in the form of a waxy solid. Mp 69-70 ° C. Yield: 95%.

³ H NMR δ (CDCl ₃ ): 0.01 (6H, 2 xs, SiCH ₃ ), 0.83 (9H, s, tBu-H), 1.13 (3H, d, J = 6 Hz, CH ₃ ), 3.14 (1H, m, H ₃ ), 3.82 (2H, s, SCH ₂ ), 4.15 (1H, m, CH ₃ CH), 4.75 (1H, d, J = 2) Hz,

₄ H), 5.36 (1 H, br s, NH), 7.28 (5H, m, Ph-H).

b) N- (6- (4-Fluorophenyl) hexyl), (3S, 4R) -4-benzylthio-3 - ((R) - (t-butyldimethylsilyloxy) ethyl) -2-oxoazetidin-1-ylacetamide

Reaction of (3S, 4R) -4-benzylthio-3 - ((R) - (t-butyldimethylsilyloxy) ethyl) -2-azetidinone with N- (6- (4-fluorophenyl) hexyl) -1-bromoacetamide by a method of as described in Example 85, the title compound was obtained as a colorless oil in 54% yield. ³ H NMR δ (CDCl ₃ ): 0.01 (6H, 2xs, SiCH ₃ ), 0.82 (9H, s, tBu-H), 1.07 (3H, d, J = 6 Hz, CH 3) , 1.3 to 1.6 (8H, m, ₂ x CH), 2.56 (2H, t, J = 2 Hz, _CH2 Ar), 3.14 (1H, m, H _3),

3.25 (2H, m, NH CH _2), 3.54, 3.81 (2H, 2x d, J = 17 Hz, _NCH2),

3.82 (2H, s, _SCH2), 4.20 (1H, m, CH ₃ CH), 4.75 (1 H, d,

J = 2Hz; ₄ H), 6.40 (1H, broad t, NH), 6.95, 7.10 (4H, 2 x m, FPh-H), 7.30 (5H, m, Ph-H).

102

c) N- (6- (4-Fluorophenyl) hexyl) - (3S, 4R) -4-benzylthio-3 - ((R) -hydroxyethyl) -2-oxoazetidin-1-ylacetamide

N- (6- (4-fluorophenyl) hexyl) - (3S, 4R) -4-benzylthio-3 - ((R) - (t-butyldimethylsilyloxy) ethyl) -2-oxoazetidine was dissolved in dry THF (50 mL). 1-ylacetamide (2.68 g, 4.57 mmol) and glacial acetic acid (0.4 mL). A solution of tetrabutylammonium fluoride in THF (6.9 mL, 6.9 mmol) was added. The solution was heated at reflux temperature, additional TBAF (2 mL, 2 mmol) was added and refluxing was continued for an additional 24 hours. The solution was poured into water (50 mL) and ethyl acetate (50 mL), the organic layer was separated and washed with water, then brine, dried over magnesium sulfate and evaporated to a brown solid residue which was recrystallized from ethyl acetate / ether, to give a cream solid (1.69 g), m.p. 102-104 ° C. Yield: 78%.

¹ H NMR δ (CDCl ₃ ): 1.2-1.7 (11, m, 4 x CH ₂ + CH ₃ ), 2.34 (1H, broad s, OH), 2.56 (2H, t, J = 8 Hz, _CH2 Ar), 3.20 (3H, m, _NHCH2 + _H3), 3.31, 3.92 (2H, 2x d, J = 17 Hz, _NCH2), 3.79 (2H , s, SCH ₂ ), 4.34 (1H, m, CH ₃ CH), 4.76 (1H, m, H ₄ ), 6.64 (1H, broad t, NH), 6.95, 7, 09 (4H, 2 * m, FPh-H), 7.25 (5H, m,

Ph-H).

Example 194

N- (6- (4-Fluorophenyl) hexyl) - (3S, 4R), 4-benzylsulphinyl-3 - ((R) hydroxyethyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2)

Reaction of N- (6- (4-fluorophenyl) hexyl) - (3S, 4R) -4-benzylthio -3 - ((R) -hydroxyethyl) -2-oxoazetidin-1-yl acetamide with mCPBA as described in Example 2 gave the title compound as a colorless solid, mp 164-170 ° C, yield 17% of theory.

^X H-NMR δ (CDC1 _3); 1.3 to 1.7 (11H, m, 4 x _CH2 + _CH3), 2.45 (1H, m, OH) 2.56 (2H, t, J = 8 Hz, _CH2 Ar), 3 25 (2H, m, NHCH ₂ ), 3.40 (1H, m, H ₃ ), 3.8-4.25 (4H, m, NCH ₂ + SOCH ₂ ), 4.33 (1H, m, CH ₃ CH), 4.69 (1H, m, H ₄ ), 6.95, 7.09 (4H, 2 m, FfPh-H), 7.2-7.5 (6H, m, Ph-H) + NH 3, tQ-Q

- Ϊ03

1782 cm ^-1 .

Determined composition: C 63.6%, H 6.7%, N 5.8%, C 26 H 33 O 2 O 4 requires: C 63.9%, H 6.8%, 5.7% N.

Example 201

N- (6-Phenylhexyl) - (4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl) acetamide

(a) Methyl (4-methoxyphenylthio-2-oxoazetidin-1-yl) acetate

To a solution of 4- (4-methoxyphenylthio) azetidin-2-one (H. Gu et al., J. Org. Chem., 55, 5655 (1990)), (11.6 g, 55 mmol), methyl bromoacetate ( 9.2 g, 60 mmol) and tetrabutylammonium bromide (1.8 g, 0.56 mmol) in dry THF (300 mL) were added atomized potassium hydroxide (3.4 g, 60 mmol), and the resulting mixture was stirred for 2 hours at room temperature. Then water (100 mL) was added. The solution was extracted with ethyl acetate (3 x 150 mL) and the combined extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (1: 1 to 2: 1) to give the product as a solid, mp 103 ° C, yield 58% of theory.

^X H-NMR δ (CDC1 _3): 2.80 (1H, dd, J = 2.2, 15 Hz, ₃ H), 3.34 (1H, dd, J = 5.15 Hz, H _{3 b),} 3 2.72 (3H, s, OCH ₃ ), 3.77, 4.29 (each 1H, d, J = 18.00 Hz, NCH ₂ ), 3.80 (3H, s, SCH ₃ ), 5.07 (1H, m, H ₄ ), 6.87 (2H, d, J = 10Hz, 1,4Ph-H), 7.35 (2H, d, J = 10Hz, 3.5Ph-H).

(b) (4- (4-Methoxyphenylthio) -2-oxoazetidin-1-yl-acetic acid)

To a solution of methyl (4-methoxyphenylthio-2-oxoazetidin-1-yl acetate (5.2 g, 18 mmol) in methanol (80 mL) was added dropwise 1 M sodium hydroxide solution (20 mL, 20 mmol) at 0 ° C. The reaction mixture was then stirred for 1 hour and evaporated to dryness, water (50 ml) was added and the solution was acidified to pH 3 with dilute hydrochloric acid, extracted with ethyl acetate (3x100 ml) and the combined extracts dried (MgSO ₄ ), evaporated and the residue was purified by recrystallization (hexane / ether) to give the product as a white solid, mp 78-79 ° C in a yield of 79% of theory.

104 ¹ H NMR δ (CDCl ₃ ): 2.80 (1H, dd, J = 1.9, 15 Hz, H _3a ), 3.34 (1H, dd, J = 5.15 Hz, H _3b ), 3.80 (3H, s, OCH ₃ ), 3.82, 4.30 (each 1H, d, J = 18.00 Hz, NCH ₂ ), 5.06 (1H, m, H ₄ ), 6, 40 (1H, broad s, NH), 6.87 (2H, d, J = 6.8 Hz, 2,6-Ph-H),

7.35 (2H, d, J = 6.8Hz, 3.5Ph-H).

c) N- (6-phenylhexyl) - (4- (4-methoxyphenylthio) -2-oxoazetidin-1)

yl) acetamide

To DCC (1.6 g, 8 mmol), hydroxybenzothiazole (1.0 g, 8 mmol) and (4- (4-methoxyphenylthio) -2-oxoazetidin-1-ylacetic acid (2.1 g, 8 mmol) were added. A solution of 6-phenylhexylamine (Morse MA et al, Cancer Research, 1846 (1991)) (1.4 g, 8 mmol) in DMF (50 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. ethyl acetate (250 mL), the precipitate was filtered off, the filtrate was washed with dilute NaHCO ₃ solution, water (2x), dried (MgSO ₄ ) and evaporated to an oily residue which was purified by flash chromatography on silica gel using hexane / ethyl acetate ( Evaporation of the appropriate fractions gave the product as a colorless oil in a yield of 77% of the theoretical yield.

¹ H NMR δ (CDCl ₃ ): 1.34-1.37 (10H, m, (CH ₂ ) ₅ ), 2.59 (2H, t, H = 7.7 Hz, CH ₂ ), 2.83 (1 H, dd, J = 2.2, 15 Hz, ₃ H), 3.18 to 3.36 (3H, m, C H _2, H _{3 b),} 3.78 (3H, s, _OCH3), 3 80.

3.99 (each 1H, d ', J = 15 Hz, NCH ₂ ), 4.95 (1H, m, H ₄ ), 6.23 (1H, broad t, NH), 6.87 (2H, d , J = 6.8 Hz, 2,6-Ph-H),

7.14-7.39 (7H, m, 3,5-Ph-H).

Example 202 (4R, SR / 4S, SS) N- (6-Phenylhexyl) - (4- (4-methoxyphenyl) sulfinyl) -2-oxoazetidin-1-ylacetamide

A solution of N- (6-phenylhexyl) - (4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl) acetamide (2.5 g, 5.8 mmol) in dichloromethane (100 mL) was cooled to -70 ° C. ° C and m-chloroperoxybenzoic acid (1.0 g, (100 mL)) was added dropwise with stirring over 60 min.

6.4 mmol) in dichloromethane at -60 ° C

105 was shaken with saturated aqueous sodium sulfite solution and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was triturated in ether and filtered. Twice recrystallization from ethyl acetate gave (R, R, R, S, S, S) -N- (6-phenylhexyl) - (4- (4-methoxyphenyl) sulfinyl) -2-oxoazetidin-1-ylacetamide (0, 1, 2, 3, 4, 4, 4). 4 g (14% of theory), m.p. 123-124 ° C.

Determined composition: 64.9% C, 6.6% H, 6.3% N, ^ 24 ^Ε 30 ^ 2θ4 requires: 65.1% C, 6.8% H, 6.3% N.

Example 203 (47 R, S 7 R, 4 S, S 7 R) N- (6-Phenylhexyl) - (4- (4-methoxyphenyl) sulfinyl) 2-oxoazetidin-1-ylacetamide

Evaporation of the filtrates from the previous example gave a waxy solid which was further purified by chromatography to give a gum as a 9: 1 mixture of diastereoisomers predominantly of the title compound.

Determined composition: 64.0% C, 6.8% H, 6.1% N, ^C 24 ^H 30 ^N 2 ° 4 ^S - 0 ° ^4EtAC requires: 64.3% C, 7.0% H, 9% N.

Example 204

N- (6phenylhexyl) - (4- (4-methoxyphenyl) sulfonyl) -2-azetidin-acetamide

A solution of N- (6-phenylhexyl) - (4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl) acetamide (2.1 g, 5 mmol) in dichloromethane (100 mL) was cooled to -70 ° C. and a solution of m-chloroperoxybenzoic acid (2.0 g, 11 mmol) in dichloromethane (100 mL) was added dropwise with stirring over 60 minutes. After an additional 2 hours at 20 ° C, the reaction mixture was shaken with saturated aqueous sodium sulfite solution and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was recrystallized from ethyl acetate to give a white solid (1.2 g, 53%), mp 93-95 ° C.

Determined composition: 62.7% C, 6.6% H, 6.2% N,

106 ε ₂ 4 ^Η 30 ^ 2θ5 ^ requires:

H, 6.6; N, 6.1%.

Example 205

N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylthio) -2-oxoazetidin-1-yl acetamide)

a) 4- (3,4-Dimethoxyphenylthio) azetidin-2-one

Sodium (0.9 g, 39 mmol) was dissolved in ethanol (150 mL) and added dropwise to the solution over 20 minutes.

3,4-dimethoxythiophenol (5.9 g, 35 mmol). the temperature was maintained between 20-25 ° C and nitrogen was bubbled through the reaction mixture. After 15 minutes, the reaction mixture was cooled to 5 ° C and a solution of 4-acetoxyazetidin-2-one (4.3 g, 33 mmol) in ethanol (50 mL) was added dropwise over 15 minutes. The temperature was maintained at 5 ° C during the addition. The mixture was then stirred at room temperature for 60 minutes. Subsequently, it was evaporated to dryness under reduced pressure. Water (400 mL) was added to the residue, the mixture was extracted with dichloromethane (2x300 mL), the extracts were dried (MgSO 4) and evaporated under reduced pressure to an oily residue. The residue was cooled to -20 ° C and triturated with ether (400 mL). Filtration gave a white solid (4.1 g, 52%) with a melting point of 145-146 ° C.

¹ H NMR δ (CDC1 _3): 2.85 (1H, m, H _3), 3.31 (1H, m, H ₃ b),

3.88 (3H, s, _O-CH3), 3.89 3H, s, _O-CH3), 4.92 (1H, dd, J =

4.9, 2.30 Hz, H ₄ ), 6.30 1H, broad singlet, NH), 6.85 (1H, d, J = 8.30 Hz, Ph-H), 7.00 (1H, d, J = 2.04 Hz, Ph-H),

7.09 (1H, dd, J = 8.25, 2.06 Hz, Ph-H).

b) Methyl (4- (3,4-dimethoxyphenyl) thio-2-oxoazetidin-1-yl) acetate

hydride sodium (0.5 g. 12 mmol) in dry DMF (10 ml) chilled on - 5 ’C a in protection nitrogen atmosphere sa po droplets in during the 15 minutes to added him solution

4- (3,4-dimethoxyphenylthio) -azetidin-2-one (3 g, 12 mmol) in dry DMF (20 mL). The temperature was maintained at -5 ° C. After 15 minutes, methyl bromoacetate (2 g, mmol) was added in one portion, and the mixture was then stirred at room temperature for 30 minutes.

107 rooms. The reaction mixture was then poured carefully into a mixture of ice water and salt, and ethyl acetate (100 mL) was added. The organic layer was washed with brine (2x), dried (MgSO ₄ ) and evaporated. The residue had a yellow oily appearance. Purified by flash column chromatography using petroleum ether / ethyl acetate to give the product as a yellow oil (0.96 g, 25%).

(c) 4- (3,4-Dimethoxyphenylthio) -2-oxoazetidin-1-yl) acetic acid

The compound was prepared according to the general preparation method of Example 201b. The product was obtained as a yellow oil.

d) N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylthio) -2-oxoazetidin-1-yl acetamide)

The compound was prepared according to the general preparation procedure of Example 201c. The product was obtained as a colorless oil.

¹ H NMR δ (CDCl ₃ ): 1.3-1.7 (8H, m, 4xCH ₂ ), 2.59 (2H, t, J = 7.6 Hz, CH ₂ Ph), 2.89 1H δ d, J = 2 Hz, H ₃ ), 3.23 (2H, m, NHCH ₂ ), 3.37 (1H, dd, J = 5, 15 Hz, H ₃ ), 3.73, 3.96 (each 1H, J = 17 Hz, NCH ₂ ), 3.87 (6H, s, 0 (¾), 4.99 (1H, m, H ₄ ),

6.16 (1H, br, s, NH); 6.8 to 7.3 (8H, m, Ph-H + (CH ₃ O) ₂ Ph-H).

Example 206 (47 R, SS / 4S, SR) -N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide

The compound was prepared according to the general preparation procedure of Examples 202 and 203. It was obtained as a yellow gum in 33% yield.

¹ H NMR δ (CDCl ₃ ): 1.35-1.62 (8H, m, CH ₂ CH ₂ CH ₂ CH ₂ ), 2.58 (2H, t, J = 7.0 Hz, CH ₂ Ph) 3.15-3.45 (4H, m, H _3a , H _3b , NH-CH ₂ ), 3.43, 3.82 (2H, dd, J = 17.0, 17.0 Hz, N- CH ₂ ),

3.90 to 3.92 (H, s, 2xOCH _3), 4.67 (1H, m, H _4), 6.75 s, NH);

6.96 to 7.29 (8H, m, Ar-H, SO-Ph- (OMe) ₂ ).

108

Example 207 (47 R, SR / 4S, SS) N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylsulphinyl) -2-oxoazetidin-1-yl) acetamide

The compound was prepared according to the general preparation procedure of Examples 202 and 203. It was obtained as a white solid, mp 126-128 ° C. The yield of the product was 26% of the theoretical yield.

¹ H NMR δ (CDCl ₃ ): 1.35-1.59 (8H, m, CH ₂ CH ₂ CH ₂ CH ₂ ), 2.59 (2H, t, J = 7.0 Hz, CH ₂ Ph) , 2.78 (1H, dd, J = 15.0, 5.0 Hz, H _3B), 3.28 (2H, m, _NH-CH2), 3.47 (1H, dd, J = 15, 0.20 Hz, H _3a ), 3.87, 4.20 (2H, dd, J = 17.0, 17.0 Hz, N-CH ₂ ), 3.93 (6H, s, 2xOCH ₃₎ ), 4.51 (1H, m, H ₄ ), 6.73 (1H, s, NH), 6.98-7.28 (8H, m, Ar-H, SO-Ph- (OMe) ₂ ) .

Example 208

N- (6-Phenylhexyl) - (4- (4-chlorophenylthio) -2-oxoazetidin-1-yl) acetamide

The compound was prepared from 4- (4-chlorophenyl) azetidin-2-one (H.Gu et al., J. Org. Chem., 55, 5655 (1990)) as generally described in Example 201. The compound was prepared in m.p. 52-54 ° C with a yield of 80% of theory.

^X H-NMR δ (CDC1 _3): 1.33 (4H, m, NCH ₂ CH ₂ (CH _{2) 2),} 1.48 (2H, m,

CH ₂ CH ₂ PhCl), 1.6.3 (2H, m, NCH ₂ CH ₂ ), 2.60 (2H, t, J = 7.4 Hz, CH ₂ PhCl), 2.88 (1H, dd, J = 2.3, 15.3 Hz, H _3a ), 3.21 (2H, m, NHCH ₂ ), 3.43 (1H, dd, J = 5.0, 15.3 Hz, H _3b ), 3 .73, 4.00 (each 1H, d, J = 16.6 Hz, NCH ₂ ), 5.12 (1H, dd, J = 2.3,

5.0 Hz, H ₄ ), 7.15 to 7.39 (Ph-H + CIPh-H).

Example 209

4- (phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

To a cooled solution (cold water water bath) of 4-phenyalazetidin-2-one (Iwata-Reuyl et al., J. Nat. Prod. 56. (8), 1373 (1993)) (1.9 g, 11 mmol) ), tetranebutylammonium bromide (0.4 g, 1.1 mmol) and 1-bromo-4-phenylbutan-2-one (Tetrahedron, 26, 5611 (1970)) (2.7 g, 11.8 mmol) ) in dry tetrahydrofuran (75 mL) was added freshly triturated hydro

109

potassium xide (1.8 g, 31 mmol). The mixture was stirred vigorously for 2 hours at ambient temperature. Water was then added, the product was extracted into ethyl acetate, dried (MgSO ₄ ) and evaporated to an oily residue. Treatment with ether / petroleum ether (b.p. 40-60 ° C) gave the product as a white crystalline solid (1.8 g, 51%), mp 62-64 ° C.

² H NMR δ (CDCl ₃ ): 2.63 (4H, m, CH ₂ CO + CH ₂ Ph), 2.85 (3H, m, CH ₂ Ph + H _3a ), 3.44 (1H, dd, J = 5.0, 15.1 Hz, H ₃ b), 3.73,

4.27 (each 1H, d, J = 18.5 Hz, NCH ₂ ), 5.21 (1H, dd, J =

2.3, 4.9 Hz, H ₄ ), 6.97-7.40 (10H, m, Ph-H).

Determined Composition: C 70.0%, H 5.9%, N 4.4%, C 19 H 19 NO 2 S requires: C 70.1%, H 5.9%, N 4.3%.

The following compounds (Examples 210-215) were prepared according to the general method of preparation given in Example 209. The (R) - and (S) -4-phenylthioazetidinones in Examples 210 and 211 were prepared as described in Basak A., Synth. Commun. 23, 1985 (1993).

Example 210 (S) -4- (Phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one Colorless oil, yield 54%.

¹ H NMR δ (CDCl ₃ ): 2.63 (4H, m, CH ₂ CO + CH ₂ Ph), 2.85 (3H, m, CH ₂ Ph + H _3a ), 3.44 (1H, dd, J = 5.0, 15.1 Hz, H _3b ), 3.73,

4.27 (each 1H, d, J = 18.5 Hz, NCH ₂ ), 5.21 (1H, dd, J = 2.3, 4.9 Hz, H ₄ ), 6.97 to 7.40 (10H, m, Ph - H).

Determined: 69.9% C, 6.0% H, 4.4% N,

C19H19NO2S requires: 70.1% C, 5.9% H, 4.3% N.

[α] D = + 92.7 ° (c 0.49, chloroform, 25 ° C).

Example 211 (R) -4- (Phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil, 63% yield.

¹ H NMR δ (CDCl ₃ ): 2.63 (4H, m, CH ₂ CO + CH ₂ Ph), 2.85 (3H, m, CH ₂ Ph + H _3a ), 3.44 (1H, dd, J = 5.0, 15.1 Hz, H ₃ b), 3.73,

110

4.27 (each 1H, d, J = 18.5 Hz, NCH ₂ ), 5.21 (1H, dd, J =

2.3, 4.9 Hz, H ₄ ), 6.97-7.40 (1OH, m, Ph-H).

Found: 69.3% C, 5.9% H, 4.4% N, C-19H19NO2S. 0.2 H ₂ 0 requires ^69! 4% C, 5.9% H, 4.3% N. [α] D = -88.7 ° (c 0.47, chloroform, 25 ° C).

Example 212

4- (2-Methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one a) 4- (2-Methoxyphenylthio) azetidin-2-one

The compound was prepared from 2-methoxythiophenol by the method generally described in Example 205a. The product was a white crystalline solid, m.p. 103-105 ° C. Yield: 81%.

NMR δ (CDCl ₃ ): 2.95 (1H, m, H _3a ), 3.39, (1H, m, H _3b ),

3.90 (1H, s, CH ₃ OPh), 4.98 (1H, dd, J = 2.4, 5.0 Hz, _H4), 6.33 (1H, s, NH), 6.96 (2H, m, 3,5- (2-CH ₃ OPh) -H), 7.39 (2H, m, 4,6- (2-CH ₃ OPh) -H).

b) 4- (2-Methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one Colorless oil, yield 76% of theory.

² H NMR δ (CDCl ₃ ): 2.59 (2H, m, CH ₂ CO), 2.81 (2H, m, CH ₂ Ph), 2.93 (1H, dd, J = 1.7, 14) 9 Hz, H _3a ), 3.36 (1H, dd, J = 5.0, 15.1 Hz, H _3b ), 3.77, 4.22 (each 1H, d, J = 18.6 Hz , _NCH2), 3.86 (3H, s, _OCH3), 5.27 (1H, dd, J = 2.3, 4.9 Hz,

H ₄ ), 6.90 (2H, m, 3,5- (2-CH ₃ OPh) -H), 7.12-7.39 (7H, m,

4,6- (2-CH ₃ OPh) -H + Ph-H).

Determined composition: C 67.6%, H 6.0%, N 3.9%, 20% ^Β 21% β 3 requires: C 67.6%, H 6.0%, N 3.9%.

Example 213

4- (3,4-dimethoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Colorless oil. Yield: 77% of theory.

¹ H NMR δ (CDCl ₃ ): 2.63 to 2.70 (2H, m, CH ₂ Ph), 2.77 to 2.90 (3H, m, COCH ₂ , H _3a ), 3.38 (1 H, dd, J = 15.03, 4.96 Hz,

111

H _3b ), 3.77 and 4.26 (1H each, d, J = 18.41 Hz, CH ₂ ), 3.86 and 3.87 (3H each, s, OCH ₃ ), 5.11 (1H δ d, J = 4.94, 2.29 Hz, H ₄ ), 6.79 (1H, d, J = 8.26, Ph-H), 6.90 to 6.98 (2H, m,

Ph-H), 7.12-7.32 (5H, m, Ph-H).

Example 214

4- (3-methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

(a) 4- (3-methoxyphenylthio) azetidin-2-one

The compound was prepared generally as described in Example 205a. The product obtained was a white crystalline solid, m.p. 55 DEG-56 DEG C. The yield of the product was 86% of the theoretical yield.

^X H-NMR δ (CDC1 _3): 2.90 (1 H, m, ₃ H), 3.38 (1H, m, H _3B), 3.80 (3H, s, _OCH3), 5.02 (1 H , dd, J = 4.94, 2.33 Hz, H ₄ ),

6.64 (1H, broad singlet, N-H), 6.85-6.90 (1H, m, Ph-H),

6.96 to 7.03 (2H, m, Ph-H); 7.23 to 7.30 (1H, m, Ph-H).

b) 4- (3-Methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

Yellow oil, yield 86%.

¹ H NMR δ (CDCl ₃ ): 2.50 to 2.97 (5H, m, CH ₂ CH ₂ , H _3a ), 3.45 (1H, dd, J = 15.0, 4.97 Hz, H _{3 b),} 3.73, 4.27 (each 1 H, d, J = 18.55 Hz, _NCH2), 3.78 (3H, s, _OCH3), 5.24 (1H, dd, J = 4.97, 2.34Hz, H ₄ ), 6.84 (1H, m, Ph-H), 6.91-6.96 (2H, m, Ph-H), 7.12-7.31 (6H, m, Ph - H).

Example 215

4- (4-Methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-όη

White crystalline solid, m.p. 57-58 ° C, yield 80%.

Determined composition: 67.4% C, 6.0% H, 4.1% N, C ₂ H ₂ NO ₃ S requires: 67.8% C, 6.0% H, 3.9% N.

Example 216 (4R, STI / MS, SS) 4- (Phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

A solution of 4-phenylthio-N- (4-phenyl-2-oxobutyl) azetidin-2-one (2.3 g, 7 mmol) in dichloromethane (80 mL) was cooled to

112

-50 to -60 ° C and a solution of m-chloroperoxybenzoic acid (1.5 g, 9 mol) in dichloromethane (60 mL) was added dropwise over 40 minutes with stirring. After an additional 2 hours at -50 to -60 ° C, an additional portion of m-chloroperoxybenzoic acid (61 mg, 0.35 mmol) was added and stirring was continued for 30 minutes. The reaction mixture was then shaken with a mixture of saturated aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution, and the organic layer was separated, dried (MgSO ₄ ) and evaporated. Crystallization from ether and then from dichloromethane / ether gave the product as a white crystalline solid, m.p.

melting point 125 up to 126 ’C. Product yield he was 27% te- oretic extract. ^X H-NMR δ (CDC1 _3): 2.78 (2H, m, _CH2 C0), 2.87 (1 H, dd, J = 4.7, 15.0 Hz, H _3a ) 2.94 (2H, m, CHPh), 3.42 (1 H, dd, J = 2.0, 15.0 Hz, H _3b ) 3.85, 4.46 (each 1H, d, J = 18.9 Hz,

CH ₂ N), 4.73 (1H, dd, J = 2.1, 4.7 Hz, H ₄ ), 7.17-7.35 (5H, m, Ph-H), 7.55 (5H) , s, SOPh-H).

Determined composition: 66.7% C, 5.7% H, 4.2% N,

H, 5.6; N, 4.1.

Example 217 (4R, 5S / 4S, 5S) -4- (Phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

The combined filtrates of Example 216 were evaporated and the residue was purified by flash chromatography (silica, ethyl acetate / petroleum ether). The product was crystallized from ether to give a white crystalline solid, m.p. 111-113 C. The yield of the product was 16% of theory.

¹ H NMR δ (CDCl ₃ ): 2.38-2.62 (2H, m, CH ₂ CO), 2.81 (2H, m, CHPh.), 3.13-3.30 (2H, m, H _3a + H _3b ), 3.73, 4.30 (each

1 H, d, J = 18.8 Hz, _CH2 N), 4.80 (1H, dd, J = 2.8, 4.8 Hz,

H ₄ ), 7.11-7.33 (5H, m, Ph-H), 7.50-7.65 (5H, m,

Sophia-H).

Determined: C 66.4%, H 5.6%, N 4.3%, C 19 H 19 NO 3 S requires: C 66.8%, H 5.6%, N 4.1%.

113

The following compounds (Examples 218 to 226) were prepared by the method generally described in Examples 216 and 217.

Example 218 (47 R, SR) -4- (Phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidine-

2-one

The compound forms a white crystalline solid with

The product yield was 26% of the theoretical yield of Example 211.

^X H-NMR δ (CDC1 _3): 2.78 (2H, m, _CH2 CO), 2.87 (1H, dd, J = 4.7, 15.0 Hz, ₃ H), 2.94 (2H , m, _CH2 Ph), 3.42 (1H, dd, J = 2.0, 15.0 Hz, H _{3 b),} 3.85, 4.46 (each 1H, d, J = 18.9 Hz .

CH ₂ N), 4.73 (1H, dd, J = 2.1, 4.7 Hz , ₄ H), 7.17 to 7.35 (5H, m, Ph-H), 7.55 (5H, s, Sophia-H). Specified composition: 66.3% C, 5.6 % H, 4.4 % N, ^ 19 ^ 19 ^ θ3 ³ 'θ' ¹³ ^ 2θ requires: : 66.3% C, 5.7 % H, 4.1 % N.. [.alpha.] _D = -309.69 DEG (c = 0.42, chloroform, at 25 ° C).

Example 219 (47 R, S 5) -4- (Phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 49-51 ° C, Yield 6% from Example 211.

^X H-NMR δ (CDC1 _3): 2.38 to 2.62 (2H, m, _CH2 C0), 2.81 (2H, m, _CH2 Ph), 3.13 3.30 (2H, m H _3a + H _3b ), 3.73, 4.30 (each 1H, d, J = 18.8 Hz, CH ₂ N), 4.80 (1H, dd, J = 2.8, 4.8 Hz,

H ₄ ), 7.11-7.33 (5H, m, Ph-H), 7.50-7.65 (5H, m,

Sophia-H).

Determined composition: 66.3% C, 5.7% H, 4.5% N, ^C 19 ^H 19 ^NO 3 ^S - ° ^15CH 3 ^CN Requires: 66.7% C, 5.6% H, 4, 6% N. [α] D = + 161.8 ° (c = 0.1, chloroform, at 25 ° C).

Example 220 (47 R, 7 R, 4 S, SS) 4- (2-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 129-131 ° C, 12% yield.

114 ¹ H NMR δ (CDCl ₃ ): 2.79 (3Η, m, H _3a + CH ₂ CO), 2.96 (2H, m, CH ₂ Ph), 3.35 (1H, dd, J = 1) Δ, 14.9 Hz, H _3b ), 3.87 (3H, s, OCH ₃ ), 3.93, 4.50 (each 1H, d, J = 18.9 Hz,

NCH ₂ ), 5.13 (1H, dd, J = 2.1, 4.7 Hz, H ₄ ), 6.93 (1H, d,

3- (2-CH ₃ OPh) -H), 7.16-7.34 (6H, Ph-H + 5- (2-CH ₃ OPh) -H),

7.49 (1 H, m, 4- (2-CH ₃ OPh) -H), 7.67 (1 H, dd, 6- (2-

CH ₃ OPh-H).

Determined composition: 64.0% C, 5.8% H, 3.9% N, ^C 20 ^H 21 ^NO 4 ^{S 1 O} 2 ^H 2 ° requires: 64.0% C, 5.8% H, 3, 7% N.

Example 221 (4R, SS / 4S, SR) -4- (2-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 85-87 ° C, yield 31% of theory.

1 H-NMR δ (CDCl ₃ ): 2.20, 2.44 (2H, m, CH ₂ CO), 2.67 (2H, m,

CH ₂ Ph), 3.26 3.45 (2H, m, H ₃ + ₃ H b), 3.39, 4.22 (each 1H, d, J = 19.1 Hz, _NCH2), 3 Δ 85 (3H, s, OCH ₃ ), 5.36 (1H, dd, J = 2.5, 4.9 Hz, H ₄ ), 6.83 (1H, d, 3- (2-CH ₃ OPh) ) H), 7.08 to 7.32 (6H, m, 5- _(2-CH3 0PH) -H + Ph-H), 7.46 (1H, m,

4- (2-CH ₃ OPh) -H), 7.76 (1H, dd, 6- (2-CH ₃ OPh) -H).

Determined composition: 64.2% C, 5.7% H, 3.7% N, 20%, 20%, 21% requires: 64.7% C, 5.7% H, 3.8% N.

Example 222 (4R, SS / 4S, SR) -4- (3,4-Dimethoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline material, m.p. 110-112 ° C, 11% yield.

Determined composition: 62.6% C, 5.8% H, 3.7% N,

C21H23NO5S requires: 62.8% C, 5.8% H, 3.5% N.

Example 223 (4R, SR / 4S, SS) 4- (3-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 94-95 ° C, yield 15%.

115

Specified composition:

C20H21NO4S requires:

64.4% C, 5.7% H, 3.9% N,

64.7% C, 5.7% H, 3.8% N.

Example 224 (47 R, SS / 4 S, S 7 R) -4- (3-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 88 DEG-88 DEG C., yield 4%.

Determined composition: 64.4% C, 5.7% H, 3.9% N, ^C 20 ^H 21 ^NO 4 ^S requires: 64.7% C, 5.7% H, 3.8% N.

Example 225 (47 R, 7 R, 4 S, SS) 4- (4-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 154-155 ° C, yield 42%.

Determined composition: 64.6% C, 5.8% H, 3.9% N,

C20H21NO4S requires: 64.7% C, 5.7% H, 3.8% N.

Example 226 (47 R, SS / 4 S, S 7 R) 4- (4-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

White crystalline solid, m.p. 67 DEG-C, yield 1.3.5%.

Determined composition: 64.6% C, 5.8% H, 3.9% N, ^C 20 ^H 21 ^NO 4 ^S requires: 64.7% C, 5.7% H, 3.8% N.

Example 227 (4-Phenylsulfonyl) -N-? (4-Phenyl-2-oxobutyl) azetidin-2-one

To a cooled solution of 4- (phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one (0.5 g, 1.54 mL) was stirred with m-chloroperoxybenzoic acid mmol in dichloromethane ( A solution (0.66 g, 3.84 mmol) in dichloromethane (25 mL) was added in 20 drops, then the cooling bath was removed and an additional portion of m-chloroperoxybenzoic acid (0.13 g, 0.75 mmol) was added to quench the reaction. . After 30 min, the mixture was shaken with a mixture of saturated aqueous si116 ričitanu solution and saturated sodium bicarbonate solution. the organic layer was separated, dried _(MgSO4) and evaporated to give an oily residue. the residue is crystallized from petroleum ether. Recrystallisation from dichloromethane The title compound was obtained as a white solid in a yield of 0.45 g (82% of theory), m.p.

C.

¹ H NMR δ (CDCl ₃ ): 2.68 (2H 3.06 (1H, dd, J = 1.9, 15)

5.2, 15.1 Hz, H _3b ), 3.94, CH ₂ N), 5.02 dd, J = 2.2,

Ph-H), 7.59-7.89 (5H, m,

Specified composition:

C19H19NO4S requires:

m, CH ₂ CO), 2.89 2H, t, CH ₂ Ph), 3 Hz, H _3a ), 3.35 (1H, dd, J = .41 (each 1H, d, J = 18.8 Hz) 1.2 Hz, H ₄ ), 7.15 to 7.34 5 H, m, SO ₂ Ph-H).

63.4% C, 5.4% H, 4.2% N,

% C, 63.9;% H, 5.4;% 3.9.

Example 228

4- (2-Methoxyphenylsulfonyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one

The compound was prepared generally as described in Example 227 and was obtained as a white crystalline solid, m.p. 122-123 ° C in 70% yield. ¹ H NMR δ (CDCl ₃ ): 2.44 (2H, m, CH ₂ CO), 2.57 (2H, m, CH ₂ Ph),

3.37 (2H, m, H _3a + H _3b ), 3.67, 4.36 (each 1H, d, J = 19.0 Hz, NCH ₂ ), 3.93 (3H, s, OCH ₃ ) 5.49 1H, dd, J = 2.7, 4.7 Hz, H ₄ ), 6.99 (1H, d, 3- (2-CH ₃ OPh) -H), 7.11 to 7, 33 (6H, m)

5- (2-CH ₃ OPh) -H + Ph-H), 7.63 (1 H, m, 4- (2-CH ₃ OPh) -H), 7.93 (1 H, dd, 6- (2) -CH ₃ OPh-H).

Determined: 61.8% C, 5.5% H, 3.7% N,

C20H21NO5S requires: 62.0% C, 5.5% H, 3.6% N.

Example 229

N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenylthio) -2-oxoazetidin-1-yl acetamide

a) 6- (3-Chlorophenyl) hexin-1-ol

A mixture of 3-chloroiodobenzene (14.3 g, 60 mmol), tetrakis (triphenylphosphine) on palladium (2.1 g, 1.8 mmol) and 5-hexin

117

The 1-ol (5.9 g, 60 mmol) in triethylamine (120 mL) was stirred for 3 hours and partitioned between water and ether. The ether layer was discarded and the aqueous layer was extracted with ether. The combined ether extracts were washed with 1 M hydrochloric acid solution and dried (Na ₂ SO ₄ ). The ether was evaporated and the residue was purified by flash chromatography on silica using dichloromethane as eluent. Evaporation of the appropriate fractions gave the resulting alcohol as an oil (11.5 g, 92%).

b) 1- (Phthalimido) -6- (3-chlorophenyl) hex-1-yne

A solution of 6- (3-chlorophenyl) hexin-1-ol (11.5 g, 55 mmol), triphenylphosphine (14.5 g, 55 mmol) and phthalimide (8.1 g, 55 mmol) in dry THF (110 mL) ) was treated with a solution of diethyl azodicarboxylate (9.6 g, 55 mmol) in THF (20 mL) for several minutes. After 16 hours, the volatiles were removed in vacuo and the residue was treated with ether. The precipitate was removed, the filtrate was evaporated and the residue was purified by flash chromatography on silica using dichloromethane as eluent. Evaporation of the appropriate fractions gave the product as a solid (16.5 g, 89%).

c) 6- (3-Chlorophenyl) hexylamine

A suspension of 1- (phthalimido) -6- (3-chlorophenyl) hex-1-yne (10 g, 30 mmol) in methanol (100 mL) was treated with platinum oxide (250 mg) and hydrogenated at 0.35 MPa. (50 psi) for 72 hours. Additional portions of catalyst were then added gradually until the theoretical hydrogen content was reached, then the mixture was filtered, and the filtrate was evaporated to a brown oily residue (9.5 g, 96%). The residue was dissolved in ethanol (100 mL) and heated with hydrazine hydrate (2.8 g, 56 mmol) at reflux temperature for 16 hours. The mixture was then cooled to 5 ° C and the precipitated solid was filtered off. Evaporation of the filtrate yielded an oily substance which was dissolved in ether, washed with water, dried (Na ₂ SO ₄ ) and evaporated. A brown oil was obtained (5.8 g, 98%).

118

d) N- [6- (4-Chlorophenyl) hexyl] -1-bromoacetamide

A solution of 6- (3-chlorophenyl) hexylamine (20 g) and Hunig's base (12.15 g) in dry dichloromethane (250 mL) was mixed with bromoacetyl bromide (19.0 g) in dichloromethane (0-5 ° C). 50 ml). After reaction and chromatography, the title compound was obtained as a white solid (20.4 g, 65%). Mp 63-65 ° C.

e) 4-Methylphenylthio-2-oxo-azetidin-1-one 4-Methylphenylthio-2-oxo-azetidin-1-one was prepared from 4-methylphenylthiol and 4-acetoxyazetidinone in the presence of sodium ethoxide in ethanol and isolated as a cream solid coloring in a yield of 4.3% of the theoretical yield. Mp 105-107 ° C.

^X H-NMR δ (CDC1 _3): 2.35 (3H, s, _CH3), 2.85, 3.32 (each 1H, dd, 2.5, 15 Hz, ₃ H), 3.34, 3 40 (1H, dd, J = 5.15Hz)

H _3b ). 4.93 (1H, m, H ₄ ), 5.03 (1H, m, H ₄ ), 6.41 (1H, broad s, NH), 7.14 (2H, d, J = 10Hz, Ph -H), 7.36 (2H, d, J = 10);

Hz, Ph-H).

f) N- [6- (4-Chlorophenyl) hexyl] -4- (4-methylphenylthio) -2-oxoazetidin-1-yl acetamide

4-Methylphenylthio-2-oxo-azetidin-1-one (2.5 g) was treated with N- [6- (4-chlorophenyl) hexyl] -1-bromoacetamide (4.3

g) in dry THF (100 mL) in the presence of 18-crown-6 ether (55 mg) and tetra-n-butylammonium bromide (1.44 g) to give N- [6- (4-chlorophenyl) after chromatography hexyl] 4- (4-methylphenylthio) -2-oxoazetidin-1-ylacetamide (2.35 g, 43%) as colorless prismatic micro-crystals, m.p. 63-65 ° C.

^X H-NMR δ (CDC1 _3): 1.28 to 1.34 (2H, m, _CH2), 1.45 -1.60 (4H, m, (CH _{2) 2),} 2.6 (2H, t, J = 7.75 Hz, _CH2), 2.89, 2.90 (each 1H, dd, J = 2.5, 15 Hz, ₃ H), 2.85 (2H, q, J = 7 5 Hz, NHCH ₂ ), 3.34, 3.40 (1H, dd, J = 5.15 Hz, H _3b ), 3.80,

3.96 (each 1H, dd, J = 19.00 Hz, NCH ₂ ), 5.03 (1H, m, H ₄ ),

6.14 (1H, broad s, NH), 7.06-7.32 (8H, m, Ph-H).

119

Example 230 (R, R / S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methyl-phenyl) -sulfinyl-2-oxo-azetidin-1-ylacetamide

Reaction of N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenylthio) 2-oxoazetidin-1-yl acetamide with mCPBA in analogy to Example 202 gave the title compound as white solid after crystallization from a mixture of diastereoisomers. prismatic crystals having a melting point of 133-134 ° C with a yield of 32% of theoretical yield, 1,790 cm ^-1 .

Determined composition: 62.3% C, 6.2% H, 6.0% N,

C24H29ClN2O3S requires: C 62.5%, H 6.3%, N 6.1%.

Example 231 (R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methyl-phenyl) -sulfinyl-2-oxo-azetidin-1-ylacetamide

Evaporation of the mother liquor from the crystallization of the product of Example 230 gave the title compound as a waxy solid with an unspecified melting point of 11%; ^{T =} c _{= 0} 791, 1690 cm ^-1 .

, The composition: 60.2% C, 6.0% H, 5.8% N, ^C 24 ^H 29 ^C1N 2 ^S · 3 ° 2 ° ^{1 H} requires 60.5% C, 6.5% H, 5. 9% N.

Example 232

N- [6- (4-Chloro-phenyl) hexyl] -4- (4-methylphenyl) sulphonyl-2-oxo-azetidin-l-yl-acetamide

Reaction of N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenylthio) 2-oxoazetidin-1-yl acetamide with mCPBA (2 equivalents) in a similar manner to Example 204 gave the title compound. in the form of white prismatic microcrystals having a melting point of 132 DEG-133 DEG C. in a yield of 71% of the theoretical yield; t = Q_Q 1794, 1690 cm ^-1 .

Determined Composition: C 60.1%, H 6.1%, N 5.9%, ^C 24 ^H 29 ^ClN 2 ° 3 ^S requires: C 60.4%, H 6.1%, N 5.9%.

Example 233 (+/-) - N- [6- (4-Chlorophenyl) hexyl] -4-phenylthio-2-oxoazitedin-1-yl acetamide hydrate

120

Reaction of (4-phenylthio-2-oxo) azetidin-1-yl acetic acid with 6- (4-chlorophenyl) hexylamine under the conditions described in Example 201 afforded the title compound as colorless crystals, m.p. C with a yield of 96% of the theoretical yield.

Determined composition: C 61.3%, H 6.3%, N 6.5%, ^C 23 ^H 27 ^ClN 2 ° ^{2S , H} 2 ° requires: C 61.5%, H 6.3%, 5% N.

The racemic compound described above (Example 233) was separated by high performance liquid chromatography with a chiral carrier to give constitutive enantiomers (Examples 234 and 235).

Example 234 (-) - N - [6- (4-Chlorophenyl) hexyl] -4-phenylthio-2-oxoazitidin-1-yl acetamide hydrate

Colorless oil, [a] D ²⁰ = - 59.9 ° (CHC1 _3, C = 0.2% w / v).

Example 235 (+) - N- [6- (4-Chlorophenyl) hexyl] -4-phenylthio-2-oxoazetidin-1-yl acetamide hydrate

Colorless oil, [α] D ² = + 56.0 ° (CHCl 3, c = 0.3% w / v).

Treatment of (+/-) - N- [6- (4-chlorophenyl) hexyl] -4-phenylthio-2-oxoazitidin-1-ylacetamide with mCPBA as described in Examples 202 and 203 affords the following sulfoxides (Examples 236 and 237).

Example 236 (R, R / S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-yl acetamide

Colorless solid, m.p. 110-111 ° C. Yield: 23%.

Determined Composition: C 61.7%, H 6.1%, N 6.3%, ^C 23 ^H 27 ^ClN 2 ° 3 ^S requires: C 61.8%, H 6.1%, 6.3% N.

121

Example 237 (R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl-2-isoazetidin-1-ylacetamide

Colorless crystals, m.p. 85-88 ° C. Yield: 30% of theory.

Found: C 61.97, H 6.1%, N 6.3%,

C23H27ClN2O3S requires: 61.8% C, 6.1% H, 6.3% N.

(R, R / S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-yl-acetamide (Example 236) was separated by high performance liquid chromatography with a chiral carrier to give constitutive enantiomers (Examples 238 and 239).

Example 238 (-) - (7 R, 7 R or S, S) -N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colorless solid. Melting point 115-118 ° C. [α] D = -238.6 ° (CHCl 3, c = 0.04% w / v).

Example 239 (+) - (7 R, 7 R or S, S) -N- [6 (4-Chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colorless solid. Mp 116-118.5 ° C. [α] _D ²⁰ = + 251.5 ° (CHCl ₃ , c = 0.03% w / v).

(7 R, S / S, 7 R) -N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide (Example 237) was separated by chiral support high performance liquid chromatography, to obtain constitutive enantiomers (Examples 240 and 241).

Example 240 (+) - (7 R, S or S, 7 R) -N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colorless solid. M.p.

116.5 'C. [a] _D ²⁰ = + 188.6 ° (CHC1 _3, C = 0.04% w /

122 vol.

Example 241 (-) - (7 R, 7 R or S, S) -N- [6 (4-Chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide

Colorless solid. Melting point 113-115 ° C. [α] _D ²⁰ = + 188.6 ° (CHCl ₃ , c = 0.04% w / v).

Example 242

N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfonyl-2-oxoazetidin-1-yl acetamide

Treatment of (7R, 7R / S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide with mCPBA in dichloromethane affords the title compound colorless crystals, m.p. 144-146 ° C, yield 92% of theory.

Determined composition: 59.6% C, 5.9% H, 6.1% N,

C23H27ClN2O4S requires: 59.7% C, 5.9% H, 6.1% N.

(+/-) - N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide (Example 242) was separated by high performance liquid chromatography with a chiral carrier to give constitutive enantiomers (Examples) 243 and 244).

Example 243 (-) - N- (6- (4-Chlorophenyl) hexyl) -4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide

Colorless solid. Melting point 106-109 ° C. [α] D ² = - 67.7 ° (CHCl ₃ , c - 0.07% w / v). Example 244 (+) - N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide

Colorless solid. M.p.

111 'C. [α] D ² = + 69.1 ° (CHCl ₃ , c = 0.08% w / v).

123

Example 245

N- [6- (4-Chlorophenyl) hexyl] -4- (4-methoxyphenylthio-2-oxoazetidin-1-ylacetamide)

The title compound was prepared by the methods described in Example 201 and isolated as colorless crystals, mp 84-86 ° C, yield 94%.

Determined composition: 62.4% C, 6.3% H, 6.1% N,

C24H29ClN2O4S requires: 62.5% C, 6.3% H, 6.1% N.

By reaction of N- [5- (4-chlorophenyl) hexyl] -4- (4-methoxyphenylthio) -

2-Oxoazetidin-1-ylacetamide with mCPBA, as described in Examples 202 and 203, gave the following sulfoxide diastereoisomers (Examples 246 and 247).

Example 246 (R, R / S, S) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methoxy-phenylsulfinyl) -2-oxoazetidin-1-ylacetamide

Colorless crystals, m.p.

Mp 116 ° C. Yield 39% of theory.

Determined composition: C 60.1%, H 6.0%, N 6.0%,

C24H29ClN2O4S requires: 60.4% C, 6.1% H, 5.9% N.

Example 247 (7R, S / S, 7R) -N- [6- (4-Chlorophenyl) hexyl] -4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-ylacetamide

Colorless crystals, m.p. 74-77 ° C. Yield 24%.

Determined composition: C 60.5%, H 6.0%, N 5.9%, ^C 24 ^H 29 ^ClN 2 ° 4 ^S requires: C 60.4%, H 6.1%, N 5.9%.

Example 248

N- [6- (4-Chloro-phenyl) hexyl] -4- (4-methoxyphenyl) -2-oxo-azetidine-1-acetamide

Treatment of (R, R, S, S) -N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-ylacetamide with mCPBA affords the title compound. in the form of colorless

124 crystals, m.p. 105-107 ° C. Yield: 91% of theory.

Designed for: 58.6% C, 5.9% H, 5.8% N, ⁽ -24.29 ^% 1Ν2θ5) requires: 58.5% C, 5.9% H, 5.7% N .

Example 249

N-Benzyl- [4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl] -acetamide Reaction of (4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl) acetic acid with benzylamine under the conditions described in the example 86, the title compound was obtained as a colorless oil in 74% yield.

¹ H NMR δ (CDCl ₃ ): 2.80, 2.86 (1H, dd, J = 2.3, 15.2 Hz,

H ₃ ), 3.29, 3.35 (1H, dd, J = 5, 15.2 Hz, H ₃ ), 3.79 (3H, s,

OCH ₃ ), 3.85, 4.05 (each 1H, d, J = 16.7 Hz, NCH ₂ ), 4.43 (2H, d, J = 5.7 Hz, NHCH ₂ ), 4.97 (1H, m, H ₄ ), 6.5 (1H, m, NH), 6.83 (2H, d, J = 8.6Hz, 4-OCH ₃ Ph-H), 7.24-7, 35 (7H, m, Ph-H, 4-OCH ₃ Ph-H); t = _{c = 0} 1,775 cm ^-1 .

Assay Composition: 64.0% C, 5.8% H, 8.1% N, 19%, 20%, 20% requires: 64.0% C, 5.7% H, 7.9% N.

Treatment of N-benzyl- [4- (4-methoxyphenylthio) -2-oxoazetidin-1-yl] acetamide with mCPBA followed by recrystallization as described in Examples 2a and 3 gives the compounds described in Examples 250 and 251.

Example 250

N-Benzyl- [4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-yl] acetamide (diastereoisomer 1)

Colorless solid, melting point 165 ° C. Yield 24%.

^X H-NMR δ (CDC1 _3): 2.75, 2.81 (1H, dd, J = 4.7, 15 Hz, ₃ H), 3.41, 3.47 (1H, dd, J = 2, 2, 15 Hz, ₃ H,), 3.86 (3H, s,

OCH ₃ ), 3.99, 4.16 (each 1H, d, J = 17.2 Hz, NCH ₂ ), 4.47 (2H, m, NHCH ₂ ), 4.55 (1H, m, H ₄₎ 7.05 (2H, m, 4-OCH ₃ Ph-H), 7.1 (1H, m, NH), 7.33 (5H, m, Ph-H), 7.47 (2H, m) .

4-OCH ₃ Ph-H); t (-, Q 1791 cm ^-1) .

Specified composition:

61.3% C, 5.4% H, 7.5% N,

125 ^C 19 ^H 2o ^N 2 4 ° ^{with the} Y ^to Duje:

61.3% C, 5.4% H, 7.5% N.

Example 251

N-Benzyl- [4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-yl] acetamide (diastereoisomer 2)

The product was a foam, 21% yield.

¹ H NMR δ (CDCl ₃ ): 3.23 (2H, m, 2xH ₃ ), 3.35, 3.89 (each

1H, d, J = 16.9 Hz, NCH ₂ ), 3.83 (3H, s, OCH ₃ ), 4.39, 4.57 (2H, 2xd W, J = 6.15 Hz, NHCH ₂ ) 4.65 (1H, m, H ₄ ), 6.90 (2H, m, 4-OCH ₃ Ph-H), 7.26-7.50 (7H, m, Ph-H, 4 OCH ₃ Ph-) H), 7.60 (1H, m, NH), t _{C = 0} 1790 cm ^-1 .

Designed for: C 60.9%, H 5.5%, N 7.4%, C 19 H 20 N 2 O 4 requires: C 61.3%, H 5.4%, N 7.5%.

Example 301

Methyl (4- (4-methoxybenzylthio) -2-oxo-azetidin-l-yl) acetate

Treatment of 4- (4-methoxybenzylthio) -azetidin-2-one (7 g) with methyl bromoacetate (5.3 g) under conditions as described in Example 29a affords the title compound as a colorless solid, m.p. 45 to 46 ° C. Yield 5.9 g (64% of theory).

Example 302

Methyl (4-methoxyphenylthio-1-azetidin-l-yl) acetate

To a solution of 4- (4-methoxyphenylthio) azetidin-2-one (H. Gu et al., J. Org. Chem., 55, 5655 (1990)) (11.6g, 55 mmol), methyl bromoacetate (9.2 g, 60 mmol) and tetrabutylammonium bromide (1.8 g, 0.56 mmol) in dry THF (300 mL) were added atomized potassium hydroxide (3.4 g, 60 mmol). The mixture was stirred for 2 hours at room temperature and then water (100 mL) was added. The solution was extracted with ethyl acetate (3 x 150 mL portions) and the combined extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (1: 1 to 2: 1) as eluent to give the product as a solid, m.p. 101-103 ° C. The yield of the product was 58% of the theoretical yield.

126 ² Η NMR (CDC1 _3): 2.80 (1H, dd, J = 2.2, 15 Hz, ₃ H), 3.34 _(1H, dd, J = 5.15 Hz, H _{3 b),} 3.72 (3H, s, OCH ₃ ), 3.77, 4.29 (each 1H, d, J = 18.00 Hz, NCH ₂ ), 3.80 (3H, s, SCH ₃ ), 5, 07 (1H, m, H ₄ ), 6.87 (2H, d, J = 10Hz, 2,6-Ph-H), 7.35 (2H, d, J = 10Hz, 3.5) Ph-H).

Example 303

Methyl (4-phenylthio-2-oxo-azetidin-l-yl) acetate

Reaction of 4-phenylthioazitidin-2-one (Iwata-Reuyl et al., J. Nat. Prod., 56. (8), 1373 (1993)), (8 g) with methyl bromoacetate (7.5 g) under the conditions described Example 1b gave the title compound as a colorless oil (6 g, 53% yield).

^X 1 HNMR (CDCl _3): 2.87 (1H, dd, H _3), 3.42 (1H, dd, H _3),

3.70 (3H, s, H _3b ), 3.75, 4.29 (each 1H, d, NCH ₂ ), 5.22 (1H, dd, H ₄ ), 7.26 to 7.46 (5H , m, Ph-H).

Example 304

Methyl [(3S, 4R) -4-benzylthio-3-chloro-2-oxoazetidin-1-yl) acetate

(a) (6S) -1-Oxo-chloro-penicillanic acid methyl ester

A solution of (6S) -1-oxo-chloro-penicillanic acid methyl ester (13.34 g, 0.0534 mol) (Tetrahedron Lett. No.11, pp. 1205-1210, 1966) in dichloromethane (200 mL) was cooled to -70 and allowed to stand. was treated with a solution of 3-chloroperoxybenzoic acid (16.76 g, 0.0534 mol) in dichloromethane (400 mL) for 1 hour, maintaining the temperature at -70 ° C. The cooling bath was then removed and the reaction stirred for 1.5 hours. An acid solution was added to the reaction mixture

Of 3-chloroperoxybenzoic acid (0.5 g) in dichloromethane (100 mL) and the mixture was stirred for 30 minutes. The reaction mixture was then washed successively with 10% aqueous sodium sulfite solution, saturated NaHCO ₃ solution, and water. It was then dried (MgSO ₄ ) and evaporated. Purification by flash chromatography (silica, petroleum ether-ethyl acetate) gave the title compound as a colorless oil, 14.1 g (99% yield).

b) Methyl 2 - [(35,47 R) -4-acetylthio-3-chloro-2-oxoazetidin-1-yl] 3-methylbut-2-enoate

A mixture of (6S) -1-oxo-chloro-penicillanic acid methyl ester (13.94 g, 0.0625 mol), acetic anhydride (24.7 mL, 0.2618 mol) and triisopropyl phosphite (14.25 g, 0.0578 mol) in benzene (150 mL) was stirred at reflux temperature for 21 hours. Then the solvents were evaporated and the residue was evaporated twice more with xylene. The orange oil was diluted with ethyl acetate (150 mL) and treated with triethylamine (0.53 g, 0.00524 mol)) with stirring for 1 hour. The reaction mixture was then washed successively with 5% aqueous citric acid solution, brine, 5% NaHCO 3, brine, dried (MgSO ₄ ) and evaporated to give a brown oil residue. Distillation of the volatile impurities and chromatography (silica, dichloromethane) followed by precipitation from petroleum ether gave the title compound as a cream solid. The yield was 6.7 g (44% of theory), mp 62-63 ° C.

c) Methyl [(3S, 4S) -4-acetylthio-3-chloro-2-oxoazetidin-1-yl] acetate

A solution of methyl 2 - [(3 S, 4 R) -4-acetylthio-3-chloro-2-oxoazetidin-1-yl] -3-methylbut-2-enoate (7.6 g, 0.026 mol) in ethyl acetate ( 300 ml) ozone oxygen was bubbled through at -65 to -70 ° C until a persistent blue color was achieved. Excess ozone was removed by subsequent bubbling with oxygen, then trimethyl phosphite (30.7 mL, 0.26 mol) was added dropwise. After 15 minutes, the solution was allowed to warm to room temperature and stirred for 19 hours. The solvents were then removed by evaporation, the residue was re-evaporated twice with toluene, then dissolved in ethyl acetate (175 ml) and stirred vigorously with a solution of p-toluenesulfonic acid (1.14 g) in water (60 ml). After dilution with water, the organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate solution and solution

128 brine, dried (MgS0 ₄₎ and evaporated. Purification by flash chromatography (silica, petroleum ether-ethyl acetate) gave the title compound as a colorless solid in a yield of 3.69 g (56%). Mp 82-83 ° C.

d) Silver [(3,5,4) -3-Chloro-1- (methoxycarbonylmethyl) -2-oxoazetidine-4-thiolate

A solution of methyl [(3 S, 4 R) -4-acetylthio-3-chloro-2-oxoazetidin-1-yl] acetate (3.64 g, 0.0145 mol) in methanol (125 mL) was added to a stirred solution under dim light. solution of silver nitrate (3.2 g, 0.0188 mol) in methanol (55 mL). Triethylamine (2.6 ml, 0.0187 mol) was then added under ice-cooling, and the reaction mixture was then stirred for 1 hour at 5-10 ° C, followed by 40 minutes at room temperature. The mixture was filtered, the solid was washed with methanol (2x) and hexane to give the title compound (4.19 g, 92%).

e) Methyl [(3 S, 4 S) -4-benzylthio-3-chloro-2-oxoazetidin-1-yl) acetate

A solution of silver [(35,47 R) -3-chloro-1- (methoxycarbonylmethyl) -2-oxoazetidine-4-thiolate (4.12 g, 0.013 mol) in acetonitrile (125 mL) was treated with benzyl bromide (2, 3, 4, 5). 3 ml, 0.0193 mol) under nitrogen and the mixture was stirred in the dark for 18 hours. Then the mixture was filtered and the filtrate was evaporated. Purification by flash chromatography (silica, petroleum ether-ethyl acetate) gave the title compound as a colorless solid, 2.93 g (75%), mp 79 ° C.

Claims (32)

PATENT CLAIMS 1. A compound of formula (I): S (O) n R ³ CH ₂ —XY in which: 1 9 R ^3a may be the same or different and each is selected from hydrogen, halogen or C 1-6 alkyl; R ³ is aryl or aryl (C 1 -C ₄ ) alkyl, which may be optionally substituted; X is a direct bond; a group X (CH 2) _m wherein X is CO, CONR ⁵ , COO, CONR ⁵ CO, or CONHO, wherein R ³ is hydrogen or C 1-4 alkyl and m is 0, or an integer from 1 to 12; or a C 1-4 alkyl alkylene chain, optionally interrupted by X; Y is an optionally substituted aryl group; and n is 0, 1 or 2. 1 9 _v The compound of claim 1, wherein R and R are each »3 3. The compound according to claim 1 or 2, wherein R is arylC ₁ _ ₃ alkyl. A compound according to any one of claims 1 to 3, Q wherein, in R, the aryl group is an optionally substituted phenyl. A compound according to any one of claims 1 to 3, Wherein, in R, the aryl group is an optionally substituted benzyl. A compound according to any one of claims 1 to 5, 130 wherein R ³ is 4-carboxybenzyl or its corresponding C (1-6) ^and alkyl or ^c (2-6) ^alkenyl ester. A compound according to any one of claims 1 to 6, wherein n is 1. 8. The compound of any one of claims 1 to 7, wherein S (O) _n R 4-carboxybenzylsulphinyl or a corresponding alkyl or C ₍₂ ^ _g alkenyl ester. 9. The compound of any of claims 1 to 8, wherein X is CO _{(CH2) m,} CONH _{(CH2) m,} CONHCO _{(CH2) m,} CONH _{(CH2) m} and C (2-12) ^Al alkylene. The compound of claim 9, wherein X is COH (CH ₂ ) g. A compound according to any one of claims 1 to 10, wherein Y is a benzene ring, optionally substituted with up to three additional substituents. The compound of claim 11, wherein Y is phenyl, optionally substituted with halogen. The compound of claim 12, wherein Y is 4-chloro or 4-fluorophenyl. A compound according to any one of claims 1 to 13, wherein the mutual configurations on the C-4 and SO moieties are R, S and S, R. A compound according to any one of claims 1 to 14, wherein the absolute configurations on the C-4 and SO moieties are R or S. A compound of formula (I) according to claim 1 selected from: 4- (benzylthio) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; 131 (4R, 5S / 4S, SS) 4- (benzylsulphinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4S, SS) 4- (Benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (benzylsulfonyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (benzylthio) -1- (2-phenyl-2-oxoethyl) azetidin-2-one; (4S, 5S, 4S, SS) 4- (Benzylsulfinyl) -1- (2-phenyl-2-oxoethyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4- (Benzylsulfinyl) -1- (2-phenyl-2-oxoethyl) azetidin-2-one; 4- (benzylthio) -1- (9-phenyl-2-oxononyl) azetidin-2-one; (47 R, S 7 R, 4 S, SS) 4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one; 4- (2-Methoxybenzylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5S / 4S, SS) 4- (2-methoxybenzylsulphinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4- (2-methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (4-fluorobenzylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5S / 4S, SS) 4- (4-fluorobenzylsulphinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 132 (4S, SS / 4S, SR) 4- (4-fluoro-benzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (4-methoxybenzylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SR / 4S, SS) 4- (4-Methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4- (4-Methoxybenzylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (phenethylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SR / 4S, SS) 4- (Phenethylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4- (phenethylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (3-Phenylpropylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SR / 4S, SS) 4- (3-Phenylpropylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4S, SR) 4- (3-Phenylpropylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; trans 3-methyl-4- (benzylthio) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5S / 4S, SS) trans 3-Methyl-4- (benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) trans 3-methyl-4- (benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; 133 N- (6-Phenylhexyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; (4 R, 4 R, 4 S, SS) N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6-Phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N-benzyl- (4-benzylthio-2-oxo-azetidin-1-yl) acetamide; (4R, 5S / 4S, SS) N-Benzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N-Benzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- (4-phenylbutyl) - (4-benzylthio-2-oxo-azetidin-1-yl) acetamide; (47 R, S 7 R / 4 S, SS) N- (4-Phenylbutyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide: (47 R, SS / 4 S, S 7 R) N- (4-Phenylbutyl) -4- (benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (9-Phenylnonyl) - (4-benzylthio-2-oxo-azetidin-1-yl) acetamide; (4R, 5S / 4S, SS) N- (9-Phenylnonyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (4R, 5S / 4S, SS) N- (9-Phenylnonyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N-methyl-N- (6-Phenylhexyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; 134 (4R, 5S / 4S, SS) N-Methyl-N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N-Methyl-N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- [6- (3,5-di-tert-butyl-4-hydroxyphenyl) hexyl] - (4-benzyltio2-oxo-azetidin-l-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- [6- (3,5-di-tert-butyl-4-hydroxyphenyl) hexyl] (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N-6- (4-methoxyphenyl) hexyl- (4-benzylthio-2-oxoazetidin1-yl) acetamide; (4R, 5S / 4S, SS) N- 6- (4-methoxyphenyl) hexyl- (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- 6- (4-methoxyphenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- (6- (4-chlorophenyl) hexyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; (47 R, S 7 R, 4 S, SS) N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzyltio2-oxo-azetidin-l-yl) acetamide; (4R, 5S / 4S, SS) N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; 135 (4R, SS / 4S, SR) N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (6- (3-chlorophenyl) hexyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; (4R, SR / 4S, SS) N- (6- (3-chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; (4R, SS / 4S, SR) N- (6- (3-Chloro-phenyl) -hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N-6- (4-hydroxyphenyl) hexyl- (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; (4R, SR / 4S, SS) and (4R, SS / 4S, SR) N- 6- (4-hydroxyphenyl) hexyl (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzyltio2-azetidin-l-yl) acetamide; (4R, SS / 4S, SR) N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzyltio2-oxoazetidin-1yl) acetamide; (4R, SS / 4S, SR) N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhex-l-yl) -4- (4-chlorobenzylthio) -2-oxoazetidin1 acetamide; (4R, SR / 4S, SS) N- (6-Phenylhex-1-yl) -4- (4-chlorobenzylsulphinyl) -2-oxoazetidin-1-ylacetamide; 136 (4R, SS / 4S, 5R) N- (6-phenylhex-1-yl) -4- (4-chlorobenzylsulphinyl) -2-oxoazetidin-1-ylacetamide; trans N- (6-Phenylhexyl) - (4-benzylthio-3-methyl-2-oxoazetidine- 1- yl) acetamide; trans N- (6-phenylhexyl) - (4-benzylsulphinyl-3-methyl- 2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhexyl) - (4-benzylsulfonyl-2-oxo-azetidin-l-yl) acetamide; N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulfonyl2-azetidin-1-yl) acetamide; N- (6- (3-chlorophenyl) hexyl) - (4-benzylsulfinyl2-azetidin-1-yl) acetamide; 4- (benzylthio) -1- (3-phenylpropyl) azetidin-2-one; (4R, 5S / 4S, SS) 4-Benzylsulphinyl-1- (3-phenylpropyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4-Benzylsulfinyl-1- (3-phenylpropyl) azetidin-2-one; 4-benzylthio-l- (2-phenethyl) azetidin-2-one; (4R, 5S / 4S, SS) 4-Benzylsulfinyl-1- (2-phenethyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) 4-Benzylsulfinyl-1- (2-phenethyl) azetidin-2-one; 4- (benzylthio) -1- (4-phenylbutyl) azetidin-2-one; (4R, 5S / 4S, SS) 4-Benzylsulphinyl-1- (4-phenylbutylazetidin-2-one); 137 p-Methoxybenzyl [(3S, 4R) -4-benzylthio-3-bromo-2-oxoazetidine- 1-yl Jacetate; (3S, 4R) -N- (6-Phenylhexyl) -1- (4-benzylthio-3-bromo- 2-oxoazetidin-1-yl) acetamide; (3S, 4R, SR) -N- (6-phenylhexyl) -4-benzylsulphinyl-3-bromo-2-oxo-azetidin-l-acetamide: (3S, 4R, SS) -N- (6-phenylhexyl) -4-benzylsulphinyl-3-bromo-2-oxo-azetidin-l-yl-acetamide; (4R, SS / 4S, SR) N- (6-Phenylhexyl) -4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide; (3 S, 4 R) -N- (6-phenylhexyl) -1- (4-benzylthio-3-bromo-2-oxo-azetidin-1-yl) acetamide; (4R, SS) -N- (6- (4-Chlorophenyl) hexyl) - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- [6- (4-phenyl) hexyl] -4- (4-methoxybenzylthio) 2-oxo-azetidin-l-yl-acetamide; N- (6- (2,4-Difluorophenyl) hexyl) - (4-benzyltio2-oxo-azetidin-l-yl) acetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxybenzylthio) 2-oxo-azetidin-l-yl-acetamide; N- (6- (3,4-Difluorophenyl) hexyl) - (4-benzyltio2-azetidin-1-yl) acetamide; N- (7-phenylhept-yl) -4-benzylthio-2-oxo-azetidin-l-yl-acetamide; N- (6- [4-chlorophenyl] hex-l-yl) - (4-metoxykarbonylbenzyltio) -2-oxo-azetidin-l-yl-acetamide; 138 N- (5-phenyl-pentyl) -4-benzylthio-2-oxo-azetidinyl-acetamide; N- (6- (4-bromo-phenyl) hexyl) -4-benzylthio-2-oxo-azetidin-l-yl-acetamide; N- (6- (4-fluorophenyl) hexyl) -4-benzylthio-2-oxo-azetidin-l-yl-acetamide; N- [5- (4-chlorophenyl) pentyl] -4-benzylthio-2-oxoazetidin-1-ylacetamide; N- [6- (2-Chlorophenyl) hexyl] -4-benzylthio-2-oxo-azetidin-l-yl-acetamide; N- (6- [4-chlorophenyl] hex-l-yl) - (4-allyloxycarbonylbenzylthio) -2-oxo-azetidin-l-yl-acetamide; N- [6- (4-methylphenyl) -hexyl] - [4-oxo-azetidine-benzylsulfinyl2-yl] acetamide; 6-Phenylhexyl (4-benzylthio-2-oxo-azetidin-1-yl) acetate; 6- (4-Chlorophenyl) hexyl- [4-benzylthio-2-oxo-azetidin-l-yl] acetate; 1- (9-Phenylnonyl) 4-benzylthio-2-oxo-azetidine; N- [6- (4-fluorophenyl) hexyl] -4- (4-methoxybenzylsulfinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1); N- [6- (4-fluorophenyl) hexyl] -4- (4-methoxybenzylsulfinyl) -2-oxoazetidin-1-ylacetamide (Diastereoisomer 2); N- (6- (2,4-difluorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1); 139 N- (6- (2,4-Difluorophenyl) hexyl) - (4-benzylsulfinyl2-oxo-azetidin-l-yl) acetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxybenzylsulfinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1); N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxybenzylsulphinyl) -2-oxo-azetidin-l-yl-acetamide; (diastereoisomer 2); N- (6- (3,4-difluorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1); N- (6-3,4-difluorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (7-phenylhept-1-yl) -4-benzylsulfinyl-2-oxoazetidin-1-ylacetamide (Diastereoisomer 1); N- (7-phenylhept-1-yl) -4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide (Diastereoisomer 2); N- (6- [4-chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1); N- (6- [4-chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (6-phenylhex-1-yl) - (4-ethoxycarbonylbenzylsulfinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 1); N- (6- (4-chlorophenyl) hex-1-yl) - (4-allyloxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (5-phenylpentyl) -4-benzylsulphinyl-2-oxoazetidinyl-1-yl acetamide; 140 N- (5- (4-chlorophenyl) pentyl) -4-benzylsulphinyl-2-oxoazetidin 1-Ylacetamide (Diastereoisomer 1); N- (5- (4-chlorophenyl) pentyl) -4-benzylsulphinyl 2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- [5- (2-Chloro-phenyl) -hexyl] -4-benzylsulfinyl-2-oxoazetidin-1-ylacetamide (Diastereoisomer 1); N- [5- (2-chlorophenyl) hexyl] -4-benzylsulphinyl-2-oxoazetidin 1-Ylacetamide; N- (6- (4-bromo-phenyl) hexyl) -4-benzylsulphinyl 2-Oxoazetidin-1-ylacetamide (Diastereoisomer 1); N- (6- (4-bromophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (6- (4-fluorophenyl) hexyl) -4-benzylsulphinyl-2-oxoazetidin-1-ylacetamide (diastereoisomer 1); N- (6- (4-fluórfenyljhexyl) -4-benzylsulphinyl-2-oxoazetidin 1-ylacetamide (diastereoisomer 2); 6-phenylhexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetate (2: 1, diastereoisomer 2: diastereoisomer 1); 6- (4-chlorophenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetate; 1- (9-Phenylnonyl) -4-benzylsulfinyl-2-oxoazetidine (diastereoisomer 1); 1- (9-Phenylnonyl) -4-benzylsulfinyl-2-oxoazetidine (75% diastereoisomer 2); 141 N- [6- (4-methylphenyl) -hexyl] - [4benzylsulphinyl-2-oxoazetidin 1-yl] acetamide; N- [6- (4-methylphenyl) -hexyl] - [4-benzylsulphinyl 2-oxoazetidin-1-yl] acetamide; N- (6- (4-chlorophenyl) hex-1-yl) - ((4-carboxybenzylsulphinyl) 2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] -4- (4-methoxybenzylsulfonyl) -2-oxoazetidin-1-ylacetamide; N- (6- (2,4-Difluorophenyl) hexyl) - (4-benzylsulfony1-2-oxo-azetidin-l-yl) acetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxybenzyl-sulfonyl) -2-oxoazetidin-l-yl-acetamide; N- (6- (3,4-Difluorophenyl) hexyl) - (4-benzylsulfonyl-2-oxo-azetidin-l-yl) acetamide; N- (7-phenylhept-yl) -4-benzylsulfonyl-2-oxoazetidin1 acetamide; N- [6- (4-chlorophenyl) hexyl] - (4- (4-carboxybenzylsulphonyl) 2-azetidin-l-yl) acetamide; N- [5- (4-chlorophenyl) pentyl] -4-benzylsulphonyl-2-oxoazetidin1 acetamide; N- [5- (2-chlorophenyl) hexyl] -4-benzylsulphonyl-2-oxoazetidin-yl-acetamide; N- (6- (4-fluorophenyl) hexyl) -4-benzylsulphonyl-2-oxoazetidin-yl-acetamide; 6-Phenylhexyl [4-benzylsulfony1-2-oxo-azetidin-1-ylJacetát; 142 6- (4-Chlorophenyl) hexyl- (4-benzylsulfonyl-2-oxoazetidin1-yl] acetate; 1- (9-Phenylnonyl) -4-benzylsulphonyl-2-oxo-azetidine; N- [6- (4-methylphenyl) -hexyl] - [4-benzylsulfonyl-2-oxoazetidin1-yl] acetamide; N- (6-phenylhexanoyl) - (4-benzylthio-2-oxo-azetidinyl) acetamide; N- (6-phenylhexanoyl) - (4-benzylsulphinyl-2-oxo-azetidinyl) acetamide; N- (5-phenyl-pentyloxy) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; N- (5-phenylpentyloxy) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (Diastereoisomer 1); N- (5-phenylpentyloxy) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (Diastereoisomer 2); 7? -N- (6- (4-chlorophenyl) hexyl) - (4-benzylthio-2-oxoazetidin1-1yl) acetamide; S-N- (6- {4-Chlorophenyl} hexyl) - (4-benzytio-2-oxoazetidin1-yl) acetamide; 47 R, S 7 -N- (6- (4-chlorophenyl) hexyl) - (4-benzysulfinyl-2-oxoazetidin-1-yl) acetamide; 45, S5-N- (6- (4-chlorophenyl) hexyl) - (4-benzysulfinyl2-oxo-azetidin-l-yl) acetamide; 47 R, S5-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); - 143 N - (6- (4-chlorophenyl) hexyl) - (4-benzylsulfonyl-2-oxoazetidin-1-yl) acetamide; 4S-N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfonyl-2-oxo-azetidin-1-y1) acetamide; 4R- (6-Phenylhexyl) - (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; 4R, S1 -N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- (6- {4-fluórfenyljhexyl) -4- (4-allyloxycarbonylbenzylthio-2-oxo-azetidin-1-yl) acetamide; N- (6- {4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1); N- (6- {4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl) hexyl) -4- (4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl} hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl} hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] - [4- (4-ethyloxycarbonylbenzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N- (6- [4-fluorophenyl] hex-l-yl) -4-carboxybenzylthio) -2-oxo-azetidin-l-yl-acetamide; N- (6- [4-fluorophenyl] hex-l-yl) - (4-methylcarboxybenzylthio) 2-oxo-azetidin-l-yl-acetamide; 144 N- [6- (4-fluorophenyl) hexyl] - [4- (4-methyloxycarbonyl-benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide; (diastereoisomer 2); N- (6- (4-chlorophenyl) hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-chlorophenyl} hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- (4-chlorophenyl} hexyl) -4- (4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) thio-2-oxoazetidin-1-yl] acetamide; N- [6- (4-fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 1); N- [6- (4-fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) thio-2-oxoazetidin-1-yl] acetamide; N- [6- (4-fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 1) N- [6- (4-fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N-2,4-dichlorobenzyl- (4-benzylthio-2-oxoazetidin-1-yl) acetamide; 145 N-2,4-Dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (Diastereoisomer 1); N-2,4-dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N-2,4-Dichlorobenzyl- (4-benzylsulfonyl-2-oxo-azetidin-l-yl) acetamide; N-3,4-Dichlorobenzyl- (4-benzylthio-2-oxo-azetidin-l-yl) acetamide; N-3,4-dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 1); N-3,4-dichlorobenzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N-3,4-dichlorobenzyl- (4-benzylsulfonyl-2-oxoazetidin-1-yl) acetamide; (3S, 4S) -N- (6- {4-fluorophenyl} hexyl) - (3-chloro-4-benzylthio-2-oxoazetidin-1-yl) acetamide; (SR, 3S, 4R) -N- (6- {4-Fluorophenyl} hexyl) - (3-chloro-4-benzylsulphinyl-2-oxo-azetidin-l-yl) acetamide; (SS, 3S, 4R) -N- (6- {4-Fluorophenyl} hexyl) - (3-chloro-4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; N- (6- (4-fluorophenyl) hexyl) - (3 S, 4 R) -4-benzylthio 3 - ((R) -hydroxyethyl) -2-oxo-azetidin-l-yl-acetamide; N- (6- (4-fluorophenyl) hexyl) - (3S, 4R) -4-benzylsulphinyl-3 - ((R) hydroxyethyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (6-Phenylhexyl) - (4- (4-methoxyphenylthio) azetidin-2-yl) 146 acetamide; (4R, 5S / 4S, SS) N- (6-phenylhexyl) - (4- (4-methoxyphenyl) sulfinyl) -2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) -N- (6-Phenylhexyl) - (4- (4-methoxyphenyl) sulfinyl) 2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhexyl) - (4- (4-methoxyphenyl) sulfonyl) -2-oxoazetidin1-yl) acetamide; N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylthio) -2-oxoazetidin-1-yl) acetamide; (4 R, 5 S, 5 S) -N- (6-phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide; (4R, 5S / 4S, SS) N- (6-phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide; N- (6-Phenylhexyl) - (4- (4-chlorophenylthio) -2-oxo-azetidin-l-yl) acetamide; 4- (phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (S) -4- (phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (R) -4- (phenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (2-methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (3,4-dimetoxypfenyltio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (3-methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (4-methoxyphenylthio) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 147 (4S, 5S / 4S, SS) 4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47?, SS / 4S, SR) 4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5R) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, SS) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5S / 4S, SS) 4- (2-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) -4- (2-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) -4- (3,4-Dimethoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (4R, 5S / 4S, SS) 4- (3-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) -4- (3-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, S 7 R, 4 S, SS) 4- (4-methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 4S, SR) -4- (4-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (phenylsulfonyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 4- (2-methoxyphenyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; 148 N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenylthio) -2-oxoazetidin-1-ylacetamide; (R, R / S, S) -N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenyl) sulfinyl-2-oxo-azetidinyl-acetamide; (R, S / S, R) -N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenyl) sulfinyl-2-oxo-azetidinyl-1-yl-acetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenyl) sulfonyl-2-oxoazetidin-1-yl acetamide; N- [6- (4-chlorophenyl) hexyl] -4-phenylthio-2-oxoazetidin-1-ylacetamide hydrate; (-) - N- [6- (4-Chlorophenyl) hexyl] -4-phenylthio-2-oxoazetidin-1-ylacetamide hydrate; (+) - N- [6- (4-Chlorophenyl) hexyl] -4-phenylthio-2-oxoazetidin 1-Ylacetamide hydrate; (R, R / S, 5) -N- [6- (4-Chlorophenyl) hexyl] -4-phenylsulfinyl- 2-Oxoazetidin-1-ylacetamide; (R, S / 5, R) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (-) - (R, R or S, 5) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (+) - (R, S or S, R) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (+) - (R, S or S, 7R) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (-) - (7 R, 7 R or S, S) -N- [6- (4-chlorophenyl) hexyl] -4-phenyl 149 sulfinyl-2-oxoazetidin-1-ylacetamide; N- [6_ (4-chlorophenyl) hexyl] -4-phenylsulfonyl-azetidin-2-acetamide; (-) - N - [6- (4-Chlorophenyl) hexyl] -4-phenylsulfonyl-2-oxoazetidin-1-ylacetamide; (+) - N - [6- (4-Chlorophenyl) hexyl] -4-phenylsulfonyl-2-oxoazetidine- 1-Ylacetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxyphenylthio) - 2-Oxoazetidin-1-ylacetamide; (R, R / S, 5) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methoxy-phenylsulfinyl) -2-oxo-azetidin-1-yl-acetamide; (R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4- (4-methoxy-phenylsulfinyl) -2-oxo-azetidin-1-yl-acetamide; N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxyphenylsulfonyl) -2-oxoazetidin-1-ylacetamide; N-benzyl- [4- (4-methoxyphenylthio) azetidin-2-yl] acetamide; N-benzyl- [4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-yl] acetamide (diastereoisomer 1); N-benzyl- [4- (4-methoxyphenylsulphinyl) -2-oxoazetidin 1-yl] acetamide (diastereoisomer 2); A compound of formula (I) according to claim 1, selected from: (4R, SS / 4S, SR) -N- (6-phenylhexyl) - (4- (4-methoxyphenylsulfinyl) - 2-oxoazetidin-1-yl) acetamide; (4R, SS / 4S, SR) -N- (6-Phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide; 150 (4R, 4S / 4S, 5S) -N- (6-phenylhexyl) - (4- (3,4-dimethoxyphenylsulfinyl) -2-oxoazetidin-1-yl) acetamide; (47 R, SS / 45, S R) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, S 5) -4- (phenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, S 5/45, S 7 R) -4- (3,4-Dimethoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, SS / 45, S R) -4- (3-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (47 R, S 5/45, S 7 R) -4- (4-Methoxyphenylsulfinyl) -N- (4-phenyl-2-oxobutyl) azetidin-2-one; (R, S / S, R) -N- [6- (4-chlorophenyl) hexyl] -4- (4-methylphenyl) sulfinyl-2-oxo-azetidinyl-acetamide; (R, S / S, R) -N- [6- (4-Chloro-phenyl) -hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (+) - (R, S or S, R) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; (-) - (R, R, or S, S) -N- [6- (4-chlorophenyl) hexyl] -4-phenylsulfinyl-2-oxoazetidin-1-ylacetamide; and (R, S / S, R) -N- [6- (4-chlorophenyl) hexyl] -4- (4-methoxyphenylsulfinyl) -2-oxoazetidin-1-ylacetamide. A compound of formula (I) according to claim 1, selected from: N- (6- (4-fluorophenyl) hexyl) -4- (4-allyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2) ); 151 N- (6- {4-fluorophenyl} hexyl) -4- (4-carboxybenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl} hexyl) -4- (4-isopropyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl} hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-fluorophenyl} hexyl) - [4- (4-ethyloxycarbonylbenzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N- (6- [4-fluorophenyl] hex-l-yl) -4-carboxybenzylthio) -2-oxo-azetidin-l-yl-acetamide; N- (6- {4-fluorophenyl} hexyl) - [4- (4-methyloxycarbonylbenzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N- (6- {4-chlorophenyl} hexyl) -4- (4-isopropyloxycarbonylbenzylsulfinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-chlorophenyl} hexyl) -4- (4-propyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- (6- {4-chlorophenyl} hexyl) -4- (4-ethyloxycarbonylbenzylsulphinyl-2-oxoazetidin-1-yl) acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] - [4- (4- (allyloxycarbonylmethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); N- [6- (4-fluorophenyl) hexyl] - [4- (4- (carboxymethyl) benzyl) sulfinyl-2-oxoazetidin-1-yl] acetamide (diastereoisomer 2); (47 R, SS / 4 S, S 7 R) 4- (Benzylsulfinyl) -1- (4-phenyl-2-oxobutyl) azetidin-2-one; L. ' 152 (47 R, SS / 4 S, S 7 R) 4- (Benzylsulfinyl) -1- (9-phenyl-2-oxononyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) N- (6-phenylhexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N-Benzyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (9-Phenylnonyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- [6- (3,5-Di-tert-butyl-4-hydroxyphenyl) hexyl] - (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide ; (4R, 5S / 4S, SS) N- 6- (4-methoxyphenyl) hexyl- (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- 6- (4-Methoxyphenyl) hexyl- (4-benzylsulphinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (4R, SS) N- (6- (4-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6- (3,5-Dichlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6- (3-chlorophenyl) hexyl) - (4-benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; (47 R, SS / 4 S, S 7 R) N- (6-Phenylhexyl) - (4- (4-ethoxycarbonyl) benzylsulfinyl-2-oxoazetidin-1-yl) acetamide; N- (6- (3,5-dichlorophenyl) hexyl) - (4-benzylsulfonyl153 2-azetidin-1-yl) acetamide; (47 R, SS / 4S, SR) 4-Benzylsulfinyl-1- (2-phenethyl) azetidin-2-one; (47 R, SS / 4 S, S 7 R) N- (6-Phenylhexyl) -4-benzylsulfinyl-3-bromo-2-oxoazetidin-1-ylacetamide; (3S, 4S, 4R) -N- (6-Phenylhexyl) -4-benzylsulphinyl-3-bromo-2-oxoazetidin-1-ylacetamide; N- (6- [4-chlorophenyl] hex-1-yl) - (4-carboxylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (6- [4-chlorophenyl] hex-1-yl) - (4-methoxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); N- (6- [4-chlorophenyl] hex-1-yl) - (4-allyloxycarbonylbenzylsulphinyl) -2-oxoazetidin-1-ylacetamide (diastereoisomer 2); and methyl [(3S, 4R) -4-benzylthio-3-chloro-2-oxoxazetidin-1-yl) acetate. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier. A compound of formula (I) for use in therapy. Use of a compound of formula (I) according to claim 1, in the manufacture of a medicament for the treatment of atherosclerosis. Use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of diabetes, hypertension, angina, post-ischemic conditions, reperfusion, rheumatoid arthritis, defeat, myocardial infarction, reperfusion injury, infections, acute and chronic inflammations, inflammatory conditions brain disorders such as Alzheimer's disease, neuropsychological disorders such as schizophrenia and psoriasis. 154 23. A method of treating a disease state associated with Lp-PLA2 enzyme activity, comprising treating a patient in need of treatment with a therapeutically effective amount of an inhibitor of said enzyme. The method of claim 23, wherein the disease state is associated with an increased action of monocytes, macrophages or lymphocytes. The method of claim 23, wherein the disease state is associated with the formation of lysophosphatidylcholine and oxidized free fatty acids. The method of claim 23, wherein the disease state is associated with lipid peroxidation in association with Lp PLA2 activity. The method of claim 23, wherein the disease state is associated with endothelial dysfunction. A compound having the formula (I) according to claim 1, in combination with another therapeutically active agent selected from anti-hyperlipidemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory and anti-hypertensive agents, for use in therapy. A process for the preparation of a compound having the formula (I) as defined in claim 1, comprising: (i) reaction of azetidone with formula (II): S (O) nR ³ in which: 155 η, R ¹ , R ² and R ³ are as defined above; with an alkylating agent of formula (III): zch ₂ xy (III) wherein Z is a displaceable group and X and alkylation conditions; means a preparation comprising i) when X CONH _{(CH2) m,} the formula (IV): method p ² , S (O) n R ³ - f / N. ABOUT R ¹ ch _{2 - about 2} h in which: n, R ¹ , R ² and R ³ with an amine having the formula (V): are specified above; NHR ⁵ (CH ₂ ) _m Y or hydroxylamine of formula (VI): ^NH 2 ° ( ^CH 2) m ^Y Y are as defined above; CONR ⁵ (CH ₂ ) _m or the reaction of an acid with (IV) (V) (VI) wherein Y and _m are as defined above, under conditions suitable for forming an amide or hydroxamate bond; iii) when X is COO (CH _{2) m,} said method comprising transesterifying another ester of formula (VII): S (O) n R ^{3 '} N CH ₂ —CO ₂ R ⁶ (VII) 156 in which: R ⁶ is (C ₁ _ ₆₎ alkyl; 1? n, R, R and R are as defined above; using conditions suitable for transesterification; iv) when X represents a group C00 (CH ₂ ) _m , said process comprising reacting a compound of formula (IV) as defined above with an alcohol Y (CH 2) _m OH or an activated derivative thereof comprising conditions suitable for v) reacting the compound to form an ester ; or with formula (VIII): (VIII) "19 3, wherein R _w, R and R @ ^J are as defined above; an alkylating agent having the formula (IX): R ³ Z (IX) a wherein R and Z are as defined above; under conditions suitable for alkylation. A compound having the formula (VII) according to claim 29. A compound having the formula (VII), according to claim 29, for use in therapy. A compound having the formula (VII), according to claim 29, selected from: methyl (4-benzylthio-2-oxoazetidin-1-yl) acetate, methyl (4- (4-methoxybenzylthio) -2-oxoazetidin-1-yl) acetate, methyl (4-methoxyphenylthio-2-oxoazetidin-1) -yl) acetate and methyl (4-phenylthio-2-oxoazetidin-1-yl) acetate.